ERK inhibitors

ABSTRACT

The present invention provides thieno[2,3-c]pyrrol-4-one compounds that inhibit activity of extracellular-signal-regulated kinase (ERK) and may be useful in the treatment of cancer.

The present invention relates to thieno[2,3-c]pyrrol-4-one compounds, orpharmaceutically acceptable salts thereof, and pharmaceuticalcompositions comprising the compounds, that inhibit activity ofextracellular-signal-regulated kinase (ERK) and may be useful fortreating cancer.

The ERK/MAPK pathway is important for cell proliferation and frequentlyobserved to be activated in many tumors. RAS genes, which are upstreamof ERK1/2, are mutated in several cancers including colorectal,melanoma, non-small cell lung cancer as well as breast and pancreatictumors. High RAS activity is accompanied by elevated ERK activity inmany human tumors. Studies have also shown that ERK is a criticalcomponent of RAS signalling. These observations support theattractiveness of the ERK1/2 signaling pathway for developing anticancertherapies in a broad spectrum of human tumors.

ERK inhibitors are known in the art; see, for example, WO2013130976.Additionally, other aminopyrimidine compounds are known in the art; see,for example, WO 2010/022121. There remains a need to provide alternativeERK inhibitors, more particularly for the treatment of cancer.Accordingly, the present invention provides ERK1/2 inhibitors which maybe useful for treating cancer.

The present invention provides a compound of the following formula:

wherein:

-   -   R¹ is

-   -   R² and R³ are independently methyl or R² and R³ can be taken        together to form cyclopropyl;    -   R⁴ is hydrogen, methyl, chloro, fluoro, or trifluromethyl; and    -   R⁵ is

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of the following formula:

wherein:

-   -   R¹ is

-   -   R² and R³ are independently methyl or R² and R³ can be taken        together to form cyclopropyl;    -   R⁴ is hydrogen, methyl, chloro, fluoro, or trifluoromethyl; and    -   R⁵ is

or a pharmaceutically acceptable salt thereof.

The present invention also provides an embodiment for a compound ofFormula I wherein R² and R³ are methyl.

The present invention also provides another embodiment for a compound ofFormula I wherein R⁴ is hydrogen.

The present invention also provides yet another embodiment for acompound of Formula I wherein R¹ is

The present invention also provides yet a further embodiment for acompound of Formula I wherein R⁵ is

Preferably, the present invention provides a compound which is6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one,or a pharmaceutically acceptable salt thereof.

As a particular embodiment, the present invention provides the compoundwhich is6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one.

The present invention provides a pharmaceutical composition comprising6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, diluent, or excipient. The present inventionprovides a pharmaceutical composition comprising6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one,and a pharmaceutically acceptable carrier, diluent, or excipient.

The present invention provides a method for treating cancer comprisingadministering to a patient in need thereof an effective amount of6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one,or a pharmaceutically acceptable salt thereof. The present inventionprovides a method for treating cancer comprising administering to apatient in need thereof an effective amount6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one.

The present invention provides6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one,or a pharmaceutically acceptable salt thereof, for use in therapy. Thepresent invention provides6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one,or a pharmaceutically acceptable salt thereof, for use in the treatmentof cancer. The present invention provides a pharmaceutical compositionfor use in treating cancer, the pharmaceutical composition comprising6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one,or a pharmaceutically acceptable salt thereof.

The present invention also provides6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-onefor use in therapy. The present invention provides6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-onefor use in the treatment of cancer. The present invention provides apharmaceutical composition for use in treating cancer, thepharmaceutical composition comprising6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one.

The present invention provides the use of6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one,or a pharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of cancer. The present invention alsoprovides the use of6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-onein the manufacture of a medicament for the treatment of cancer.

The present invention provides6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-onein a crystalline form. The present invention also provides6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-onein a crystalline form characterized by a X-ray powder diffractionpattern having characteristic peaks, in 20±0.2°, occurring at 19.3° incombination with one or more of the peaks selected from the groupconsisting of 15.5°, 17.1°, 18.0°, 20.2°, 21.5° and 22.1°.

Furthermore, the present invention provides preferred embodiments of themethods and uses as described herein, in which cancer is selected fromthe group consisting of melanoma, colorectal cancer, pancreatic cancer,and non-small cell lung cancer. Preferred cancers are colorectal cancer,pancreatic cancer, and non-small cell lung cancer.

The present invention also provides6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one,or a pharmaceutically acceptable salt thereof, for use in simultaneous,separate or sequential administration in combination with one or morechemotherapy agents in the treatment of cancer. Preferred chemotherapyagents for such a combination are a pan-RAF inhibitor compound, moreparticularly1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea),a CDK4/6 inhibitor compound, more particularly palbociclib, ribociclib,or[5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine,or a pharmaceutically acceptable salt thereof, or an anti-VEGFR2antibody, more particularly ramucirumab. Additional preferredchemotherapy agents for such a combination are a TGF-beta receptorkinase inhibitor compound, more particularly galunisertib (see WO2004/048382), an ALK-5 kinase inhibitor, more particularly EW-7197, aMEK inhibitor compound, more particularly cobimetinib or trametinib, ora Notch inhibitor compound, more particularly4,4,4-trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]butanamide(see WO 2013/016081). Further additional preferred chemotherapy agentsfor such a combination are a PD-L1 (Programmed death-ligand 1) inhibitoror a PD-1 (Programmed death 1) inhibitor.

The present invention preferably contains compounds of Formula I withthe following substituents:

a) R1 is

b) R2 is methyl;

c) R3 is methyl;

d) R4 is hydrogen; or

e) R5 is

More preferably, the present invention contains compounds of Formula Iwith the following combinations of substituents:

a) R² and R³ are methyl;

b) R² is methyl, R³ is methyl, and R⁴ is hydrogen;

c) R¹ is

and R⁵ is

d) R² is methyl, R³ is methyl, R⁴ is hydrogen, and R¹ is

e) R² is methyl, R³ is methyl, R⁴ is hydrogen, and R⁵ is

or

f) R² is methyl, R³ is methyl, R⁴ is hydrogen, and R¹ is

and R⁵ is

As used above, and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings:

A “pharmaceutically acceptable carrier, diluent, or excipient” is amedium generally accepted in the art for the delivery of biologicallyactive agents to mammals, e.g., humans

“Pharmaceutically acceptable salts” or “a pharmaceutically acceptablesalt” refers to the relatively non-toxic, inorganic and organic salt orsalts of the compound of the present invention.

“Effective amount” means the amount of the compound, or pharmaceuticallyacceptable salt thereof, of the present invention or pharmaceuticalcomposition containing a compound, or pharmaceutically acceptable saltthereof, of the present invention that will elicit the biological ormedical response of or desired therapeutic effect on a tissue, system,animal, mammal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician.

The terms “treatment,” “treat,” “treating,” and the like, are meant toinclude slowing or reversing the progression of a disorder. These termsalso include alleviating, ameliorating, attenuating, eliminating, orreducing one or more symptoms of a disorder or condition, even if thedisorder or condition is not actually eliminated and even if progressionof the disorder or condition is not itself slowed or reversed.

It will be understood by the skilled artisan that compounds of thepresent invention are capable of forming salts. The compounds of thepresent invention contain basic heterocycles, and accordingly react withany of a number of inorganic and organic acids to form pharmaceuticallyacceptable acid addition salts. Such pharmaceutically acceptable acidaddition salts and common methodology for preparing them are well knownin the art. See, e.g., P. Stahl, et al., HANDBOOK OF PHARMACEUTICALSALTS: PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH, 2008); S. M.Berge, et al., “Pharmaceutical Salts”, Journal of PharmaceuticalSciences, Vol 66, No. 1, January 1977.

The compounds of the present invention are preferably formulated aspharmaceutical compositions administered by a variety of routes.Preferably, such compositions are for oral administration. Suchpharmaceutical compositions and processes for preparing the same arewell known in the art. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OFPHARMACY (A. Gennaro, et al., 21^(st) ed., Mack Publishing Co., 2005).

The compounds of the present invention are generally effective over awide dosage range. For example, dosages per day normally fall within thedaily range of about 1 to 2000 mg. Preferably such doses fall within thedaily range of 50 to 1000 mg. More preferably such doses fall within thedaily range of 125 to 400 mg. In some instances dosage levels below thelower limit of the aforesaid ranges may be more than adequate, while inother cases still larger doses may be employed, and therefore the abovedosage ranges are not intended to limit the scope of the invention inany way. It will be understood that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound or compoundsadministered, the age, weight, and response of the individual patient,and the severity of the patient's symptoms.

The skilled artisan will appreciate that certain compounds of thepresent invention contain at least one chiral center. The presentinvention contemplates all individual enantiomers or diastereomers, aswell as mixtures of the enantiomers and diastereomers of said compoundsincluding racemates. It is preferred that compounds of the presentinvention containing at least one chiral center exist as singleenantiomers or diastereomers. The single enantiomers or diastereomersmay be prepared beginning with chiral reagents or by stereoselective orstereospecific synthetic techniques. Alternatively, the singleenantiomers or diastereomers may be isolated from mixtures by standardchiral chromatographic or crystallization techniques.

The designation of “isomer 1” in a compound name represents that thecorresponding intermediate or compound of the present invention is thefirst of two eluting enantiomers when a mixture of a pair of enantiomersis separated by chiral chromatography. The designation of “isomer 2” ina compound name represents that the corresponding intermediate orcompound of the present invention that is the second of two elutingenantiomers when the mixture of a pair of enantiomers is separated bychiral chromatography.

The compounds of the present invention can be prepared according tosynthetic methods well known and appreciated in the art. Suitablereaction conditions for the steps of these reactions are well known inthe art and appropriate substitutions of solvents and co-reagents arewithin the skill of the art. Likewise, it will be appreciated by thoseskilled in the art that synthetic intermediates may be isolated and/orpurified by various well known techniques as needed or desired, and thatfrequently, it will be possible to use various intermediates directly insubsequent synthetic steps with little or no purification. Furthermore,the skilled artisan will appreciate that in some circumstances, theorder in which moieties are introduced is not critical. The particularorder of steps required to produce the compounds of the presentinvention is dependent upon the particular compound being synthesized,the starting compound, and the relative liability of the substitutedmoieties, as is well appreciated by the skilled chemist. Allsubstituents, unless otherwise indicated, are as previously defined, andall reagents are well known and appreciated in the art.

As used herein, the following terms have the meanings indicated: “ACN”refers to acetonitrile; “DCM” refers to dichloromethane; “DMF”represents N,N-dimethylformamide; “DMSO” refers to dimethyl sulfoxide;“DTT” refers to dithiothreitol; “EDTA” refers toethylenediaminetetraacetic acid; “EGTA” refers to ethylene glycoltetraacetic acid; “ELISA” refers to enzyme-linked immunosorbent assay;“EtOAc” refers to ethyl acetate; “EtOH” refers to ethanol; “FBS” refersto fetal bovine serum; “HBSS” refers to Hank's Balanced Salt Solution;“IC₅₀” refers to half maximal inhibitory concentration; “IVTI” refers toin vivo target inhibition; “MS” refers to mass spectroscopy; “MeOH”refers to methanol; “NMR” refers to nuclear magnetic resonance; “PBST”refers to phosphate buffered saline containing Tween-20; “THF” refers totetrahydrofuran; “UVW” refers to ultra-violet wavelength, and “XRD”refers to X-ray diffraction.

Unless noted to the contrary, the compounds illustrated herein are namedand numbered using either ACDLABS or Accelrys Draw 4.1.

Compounds of the present invention may be synthesized as illustrated inthe following schemes, where R¹, R², R³, R⁴, and R⁵ are as previouslydefined.

Scheme 1: Synthesis of Compounds of Formula I

Scheme 1 illustrates the general synthesis of compounds of Formula I.Compound 1 is reacted with a suitably substituted Compound 2 underwell-known aromatic substitution or coupling reaction conditions toprovide a compound of Formula I. More specifically, Compound 1 isreacted with Compound 2 at elevated temperature in the presence of asuitable base such as sodium hydride, isopropylmagnesium chloride,cesium carbonate, potassium carbonate or tert-butoxide. Optionally,introduction of a suitable ligand agent such as4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl,and a suitable catalyst such as palladium(II)acetate,tris(dibenzylideneacetone)dipalladium(0) orchloro[2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II)in an appropriate solvent such as 1,4-dioxane or tert-butyl alcohol mayalso provide a compound of Formula I.

Scheme 2: Synthesis of compounds of Formula I when R⁵ is3-methoxy-1H-pyrazol-4-yl or 3-cyclopropyl-1H-pyrazol-4-yl

Scheme 2 illustrates the synthesis of compounds of Formula I when R⁵ is3-methoxy-1H-pyrazol-4-yl or 3-cyclopropyl-1H-pyrazol-4-yl. Compound 1is reacted with Compound 3, which is a suitably substituted pyrazoleamine with a suitable nitrogen protecting groups such astert-butyloxycarbonyl, under well-known coupling reaction conditions aspreviously described to provide Compound 4. Compound 4 is furtherreacted with a suitable nitrogen de-protecting agent such as hydrogenchloride or trifluoroacetic acid in a suitable solvent such as1,4-dioxane or MeOH to provide a compound of Formula I when R⁵ is3-methoxy-1H-pyrazol-4-yl or 3-cyclopropyl-1H-pyrazol-4-yl.

Scheme 3: Alternative Synthesis of Compounds of Formula I

Scheme 3 illustrates an alternative synthesis of compounds of Formula I.Compound 5 is reacted with (2-bromoethoxy)-tert-butyldimethylsilane inthe presence of a suitable base such as sodium hydride in a suitablesolvent such as DMF to provide Compound 6. Compound 6 is then reactedwith a suitably substituted Compound 2 (R⁵—NH₂) under well-knowncoupling reaction conditions as previously described to provide Compound7. Compound 7 is reacted with a suitable de-protecting agent such asacetic acid in a suitable solvent such as a mixture of THF and water toprovide Compound 8. Compound 8 is further reacted with methanesulfonylchloride in a suitable solvent such as DMF in the presence of a suitablebase such as triethylamine to provide Compound 9. Compound 9 is reactedwith a suitable amine in a suitable solvent such as ACN to provide acompound of Formula I.

Scheme 4: Synthesis of Compound 1

Scheme 4 illustrates the method for the synthesis of Compound 1.Compound 10 is reacted with a suitable bromination agent such asN-bromosuccinimide in a suitable solvent such as ACN to provide Compound11. Compound 11 is reacted with a suitable base such as sodium hydrideor sodium hydroxide, and a suitable N-alkylation agent such as4-(2-chloroethyl)morpholine to provide Compound 12. Compound 12 isreacted with bis(pinacolato)diboron, a suitable base such as potassiumacetate, and a suitable catalyst such as(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) chloride in asuitable solvent such as 1,4-dioxane under an elevated temperature toprovide Compound 13. Compound 13 is reacted with a suitably substitutedpyrimidine compound such as 2,4-dichloro-5-methylpyrimidine, a suitablebase such as potassium carbonate, a suitable catalyst such astetrakis(triphenylphosphine)palladium in a suitable solvent such as amixture of 1,4-dioxane and water under an elevated temperature toprovide Compound 1.

Scheme 5: Alternative Synthesis of Compound 1

Scheme 5 illustrates an alternative method for the synthesis ofCompound 1. Compound 11 is reacted with a suitable nitrogen protectingagent such di-tert-butyldicarbonate in a suitable solvent such as ACN inthe presence of a suitable base such as N,N-diisopropylethylamine toprovide Compound 14. Compound 14 is reacted with bis(pinacolato)diboronunder well-known coupling reaction conditions as previously described toprovide Compound 15. Compound 15 is reacted with a suitably substitutedpyrimidine compound under well-known coupling reaction conditions aspreviously described to provide Compound 16. Compound 16 is de-protectedwith a suitable de-protecting agent such as trifluoroacetic acid orhydrogen chloride in a suitable solvent such as DCM or 1,4-dioxane toprovide Compound 17. Compound 17 is reacted with a suitable alkylationagent such as 4-(2-bromoethyl)morpholine in a suitable solvent such asN-methylpyrrolidone in the presence of a suitable base such as sodiumhydride to provide Compound 1.

Preparation 1 6,6-Dimethylthieno[2,3-c]furan-4-one

Cool a solution of 3-thiophenecarboxylic acid (250 g, 1.95 mol) in THF(9750 mL) to −70° C. in a 20 L 3-neck flask. To this solution, addn-butyl lithium (2.5 M in hexane, 1872 mL, 4.68 mol) slowly whilemaintaining the temperature below −55° C. Stir the reaction mixture forone hour at −70° C. Add acetone (187 mL, 2.55 mol) slowly at −70° C.Allow the reaction mixture to warm to 0° C. and stir for three hours at0° C. To the resulting solution, add 4 M HCl (1500 mL) at 0° C. andallow the reaction mixture to warm to room temperature. Stir theresulting mixture overnight. Filter the reaction mixture through adiatomaceous earth pad and wash the pad with toluene (3×500 mL).Concentrate the filtrate under reduced pressure. Dissolve the resultingcrude residue in toluene (3750 mL) and water (250 mL) and add p-toluenesulfonic acid (100.1 g, 0.526 mol) at room temperature. Reflux thereaction mixture for 16 hours at 100° C. Cool the reaction to roomtemperature and concentrate under reduced pressure at 50° C. Dissolvethe resulting residue in water and extract with EtOAc (2×10 L). Wash theorganic layer with saturated aqueous sodium bicarbonate and water. Drythe organic layer over anhydrous sodium sulfate, filter and concentratethe filtrate under reduced pressure at 50° C. to provide the titlecompound 200 g (61%) as brown viscous liquid. MS (m/z): 169 (M+1).

Preparation 2 6,6-Dimethyl-5H-thieno[2,3-c]pyrrol-4-one

Charge a 5 L autoclave with a solution of6,6-dimethylthieno[2,3-c]furan-4-one (150 g, 0.891 mol) in ammoniumhydroxide (1000 ml). In a closed environment, bring the reaction mixturecarefully to a temperature of 200° C. and stir for four hours at 200° C.After four hours, cool the reaction mixture to room temperature andrelease the ammonia gas. Extract the reaction mixture with DCM (3×750mL). Wash the organic layer with water (1×750 mL), and dry overanhydrous sodium sulfate, filter and concentrate the filtrate underreduced pressure at 50° C. to give the title compound 100 g (67%). MS(m/z): 168 (M+1).

Preparation 3 Methyl 2-bromothiophene-3-carboxylate

Treat a solution of 2-bromo-3-thiophenecarboxylic acid (10.1 g, 49 mmol)in MeOH (100 mL) with sulfuric acid (2.5 mL, 45 mmol). Heat the reactionto reflux overnight. Concentrate the mixture under reduced pressure toremove the organic solvent and pour the resulting mixture into ice coldwater. Extract the cold solution with EtOAc. Wash the combined organicextracts with water followed by a saturated aqueous sodium bicarbonatesolution. Dry the organic solution over anhydrous sodium sulfate, filterand concentrate the filtrate under reduced pressure to give the titlecompound 10.77 g (100%). ¹H NMR (400.15 MHz, DMSO-d₆) δ 7.65 (d, J=6 Hz,1H), 7.34 (d, J=6 Hz, 1H), 3.78 (s, 3H).

Preparation 4 Methyl 2-cyanothiophene-3-carboxylate

Heat a mixture of methyl 2-bromothiophene-3-carboxylate (28 g, 128 mmol)and copper cyanide (15 g, 167 mmol) in N-methylpyrrolidone (130 mL) to120° C. overnight. Cool the reaction to room temperature and dilute withEtOAc. Wash the organic solution with saturated NaCl, dry over anhydroussodium sulfate, filter and concentrate the filtrate under reducedpressure. Purify the residue by silica gel column chromatography elutingwith 25% EtOAc in hexane to give the title compound 15.2 g (71%). ¹H NMR(400.15 MHz, DMSO-d₆) δ 8.10 (d, J=5 Hz, 1H), 7.58 (d, J=5 Hz, 1H), 3.86(s, 3H).

Preparation 5 Spiro[5H-thieno[2,3-c]pyrrole-6,1′-cyclopropane]-4-one

Treat a −70° C. solution of methyl 2-cyanothiophene-3-carboxylate (13.7g, 79 mmol) and titanium tetra(isopropoxide) (24.8 g, 87.4 mmol) indiethyl ether (330 mL) with a solution of ethylmagnesium bromide (3 M indiethyl ether, 58 mL, 175 mmol). Stir the reaction mixture for 60minutes. Remove the cooling bath and allow the mixture to slowly warm toroom temperature over one hour. Add boron trifluoride etherate (22.6 mL,159 mmol) and stir the mixture for an additional one hour. Quench thereaction with 1 N hydrochloric acid (240 mL) and stir overnight.Separate the organic layer and back extract the aqueous layer withadditional ether. Combine the organic extracts and wash with saturatedaqueous sodium bicarbonate and saturated NaCl. Dry the organic solutionover anhydrous sodium sulfate, filter and concentrate the filtrate underreduced pressure. Purify the residue by HPLC on a C18 column (Column:275 g; Mobile Phase: A) 0.10% formic acid in water, B) 0.10% formic acidin ACN; Gradient: 5-35% B; Flow Rate: 80 mL/min) to give the titlecompound 1.02 g (35%). ¹H NMR (400.15 MHz, DMSO-d₆) δ 8.43 (bs, 1H),7.53 (d, J=5 Hz, 1H), 7.12 (d, J=5 Hz, 1H), 1.51 (m, 2H), 1.38 (m, 2H).

Preparation 6 2-Bromo-6,6-dimethyl-5H-thieno[2,3-c]pyrrol-4-one

To a 20 L flask containing 6,6-dimethyl-5H-thieno[2,3-c]pyrrol-4-one(835 g, 4.99 mol) add ACN (10000 mL) and cool the solution to 10° C. AddN-bromosuccinimide (444.4 g, 2.49 mol) in four equal portions to thereaction mixture and stir for six hours at 25° C. Concentrate thereaction mixture under reduced pressure and slurry the resultingcompound in water and extract with EtOAc (3×4.1 L). Wash the combinedorganic extracts with water (3×4.1 L) and saturated NaCl (4.1 L), dryover anhydrous sodium sulfate and filter. Store the organic solution forcombination with additional batches.

Using the same process as above, prepare two additional batches startingwith 650 g and 835 g 6,6-dimethyl-5H-thieno[2,3-c]pyrrol-4-onerespectively. Combine the organic solutions from all three runs andconcentrate under reduced pressure at 50° C. to yield2-bromo-6,6-dimethyl-5H-thieno[2,3-c]pyrrol-4-one as brown stickymaterial. Slurry the resulting product in diethyl ether/hexane (2:1 v/v)and filter to yield the title compound 1542 g (45%). MS (m/z): 246/248(M+1/M+3).

The following compound is prepared essentially by the method ofPreparation 6.

Prep. No. Compound Name Structure MS (m/z): 72-Bromospiro[5H-thieno[2,3-c]pyrrole-6,1′- cyclopropane]-4-one

244/246 (M + 1/M + 3)

Preparation 8 4-(2-Bromoethyl)morpholine hydrobromide

Treat a solution of triphenylphosphine dibromide (124 g, 293 mmol) inDCM (2.44 L) with a solution of 4-morpholineethanol (32 g, 244 mmol) inDCM (60 mL) dropwise over one hour while maintaining the reactiontemperature below 25° C. Stir the mixture overnight at room temperature.Conduct an additional reaction as above starting with4-morpholineethanol (10 g, 76 mmol), scaling the reagents appropriately.Combine the reaction mixtures and collect the solids by vacuumfiltration to give the title compound 76.7 g (84%). ¹H NMR (399.8 MHz,DMSO-d₆) δ 4.05 (m, 2H), 3.84 (m, 2H), 3.78 (t, J=7 Hz, 1H), 3.67 (t,J=7 Hz, 2H), 3.56 (m, 2H), 3.26 (m, 2H).

Preparation 9 tert-Butyl2-bromo-6,6-dimethyl-4-oxo-thieno[2,3-c]pyrrole-5-carboxylate

Synthetic Method 1:

Treat a solution of 2-bromo-6,6-dimethyl-5H-thieno[2,3-c]pyrrol-4-one(25 g, 102 mmol), 4-dimethylaminopyridine (1.25 g, 10 mmol) andN,N-diisopropylethylamine (24 mL, 138 mmol) in ACN (481 mL) withdi-tert-butyldicarbonate (35 g, 162 mmol). Stir the mixture overnight atroom temperature. Concentrate the mixture under reduced pressure. Dilutethe mixture with hexane, filter the mixture through a silica gel pad andelute the pad with hexane followed by 20% DCM in hexane. Concentrate thefiltrate to dryness to give the title compound 36.5 g (93%) as an orangeoil. ¹H NMR (399.8 MHz, CDCl₃) δ 7.19 (s, 1H), 1.74 (s, 6H), 1.58 (s,9H).

Synthetic Method 2:

Treat a solution of 2-bromo-6,6-dimethyl-5H-thieno[2,3-c]pyrrol-4-one(200 g, 813 mmol), N,N-dimethylpyridin-4-amine (9.93 g, 81 mmol) anddi-tert-butyldicarbonate (266 g, 1219 mmol) in ACN (2 L) dropwise withN,N-diisopropylethylamine (213 mL, 1219 mmol). Stir the mixture at roomtemperature for four hours. Heat the reaction to 30° C. for two hours.Cool the mixture to room temperature and stir overnight. Concentrate themixture under reduced pressure. Dilute the mixture with EtOAc and washthe resulting organic solution twice with water (300 mL) followed bysaturated NaCl (300 mL). Dry the organic solution over anhydrous sodiumsulfate, filter and concentrate the filtrate under reduced pressure.Purify the residue on a silica gel pad eluting with a gradient from0-20% EtOAc in hexane to give the title compound 253 g (90%). MS (m/z):290/292 (M-isobutene+1/M-isobutene+3). ¹H NMR (399.8 MHz, CDCl₃) δ 7.19(s, 1H), 1.74 (s, 6H), 1.58 (s, 9H).

Preparation 10 tert-Butyl6,6-dimethyl-4-oxo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[2,3-c]pyrrole-5-carboxylate

Degas a mixture of tert-butyl2-bromo-6,6-dimethyl-4-oxo-thieno[2,3-c]pyrrole-5-carboxylate (114 g,329 mmol), bis(pinacolato)diboron (125 g, 494 mmol) and potassiumacetate (97 g, 988 mmol) in 1,4-dioxane (1.6 L) with nitrogen for 10minutes. Add (1,1′-bis(diphenylphosphino)ferrocene)palladium(II)chloride (5.38 g, 6.6 mmol) and heat the mixture at 90° C. for fourhours. Cool the reaction to room temperature and filter through aCELITE® pad. Concentrate the filtrate and then treat the residue with10% EtOAc in hexane. Collect the precipitate by vacuum filtration togive the title compound 65.8 g (40%). MS (m/z): 338 (M-isobutene+1).

Preparation 11 tert-Butyl2-(2-chloropyrimidin-4-yl)-6,6-dimethyl-4-oxo-thieno[2,3-c]pyrrole-5-carboxylate

Synthetic Method 1:

Degas a mixture of tert-butyl2-bromo-6,6-dimethyl-4-oxo-thieno[2,3-c]pyrrole-5-carboxylate (36 g, 104mmol), bis(pinacolato)diboron (59.8 g, 235 mmol) and potassium acetate(33.2 g, 338 mmol) in 1,4-dioxane (520 mL) with nitrogen for 10 minutes.Add (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) chloride (4.45g, 5.5 mmol) and heat the mixture to 90° C. Heat the mixture at 90° C.for two hours. Cool the reaction to room temperature and stir for threehours. Add 2,4-dichloropyrimidine (22 g, 145 mmol) followed by asolution of potassium carbonate (20.4 g, 147 mmol) in water (83 mL).Degas the resulting mixture with nitrogen for 10 minutes. Addtetrakis(triphenylphosphine)palladium (1.59 g, 1.38 mmol) and heat themixture to 90° C. for two hours. Cool the mixture to room temperatureand filter through a pad of CELITE®. Wash the filtrate with threeportions water and one portion of saturated NaCl. Concentrate theorganics under reduced pressure. Purify the residue by silica gel columnchromatography eluting with a gradient from 0-25% EtOAc in DCM to givethe title compound 11 g (59%). MS (m/z): 324 (M-isobutene+1).

Synthetic Method 2

Degas a mixture of tert-butyl6,6-dimethyl-4-oxo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[2,3-c]pyrrole-5-carboxylate(11.7 g, 30 mmol), 2,4-dichloropyrimidine (13 g, 89 mmol), potassiumcarbonate (20.4 g, 147 mmol), and water (50 mL) in 1,4-dioxane (100 mL)with nitrogen for 10 minutes. Add tetrakis(triphenylphosphine)palladium(2.58 g, 2.2 mmol) and heat the mixture to 87° C. for 1.5 hours. Coolthe mixture to room temperature. Dilute the mixture with EtOAc (1 L) andwash the resulting solution with water and saturated NaCl. Dry theorganic solution over anhydrous sodium sulfate, filter and concentratethe filtrate under reduced pressure. Treat the residue with 30% EtOAc inhexane (200 mL) and collect the resulting precipitate by vacuumfiltration to give the title compound 7.6 g (67%). MS (m/z): 324(M-isobutene+1).

Preparation 122-(2-Chloropyrimidin-4-yl)-6,6-dimethyl-5H-thieno[2,3-c]pyrrol-4-one

Stir a mixture of tert-butyl2-(2-chloropyrimidin-4-yl)-6,6-dimethyl-4-oxo-thieno[2,3-c]pyrrole-5-carboxylate(6.36 g, 16.7 mmol) and trifluoroacetic acid (25 mL) in DCM (25 mL) atroom temperature for two hours. Concentrate the mixture under reducedpressure and dilute the residue with DCM. Partition the mixture withsaturated aqueous sodium bicarbonate solution and collect the solidsfrom the biphasic emulsion. Wash the solids with ether and dry undervacuum at 50° C. overnight to give the title compound 4.65 g (99%). MS(m/z): 280 (M+1).

Preparation 132-(2-Chloropyrimidin-4-yl)-6,6-dimethyl-5H-thieno[2,3-c]pyrrol-4-onehydrochloride

Heat a solution of tert-butyl2-(2-chloropyrimidin-4-yl)-6,6-dimethyl-4-oxo-thieno[2,3-c]pyrrole-5-carboxylate(66.7 g, 176 mmol) and hydrogen chloride (4 M in 1,4-dioxane, 263 mL,1054 mmol) in 1,4-dioxane (585 mL) at 30° C. for five hours. Remove theheating element and stir the mixture at room temperature overnight.Slowly add hexane (800 mL) to the reaction mixture. Stir the resultingslurry for 10 minutes and collect the solids by vacuum filtration. Drythe solid under vacuum to give the title compound 56 g (100%). MS (m/z):280 (M+1).

Preparation 142-Bromo-6,6-dimethyl-5-(2-morpholinoethyl)thieno[2,3-c]pyrrol-4-one

Add sodium hydroxide (160 g, 4 mol) to water (250 mL) and stir themixture until a clear solution is produced. Add 1,4-dioxane (2 L)followed by 2-bromo-6,6-dimethyl-5H-thieno[2,3-c]pyrrol-4-one (215 g,874 mmol), tetrabutylammonium iodide (300 g, 812 mmol) and4-(2-chloroethyl)morpholine hydrochloride (300 g, 1564 mmol). Heat themixture at 80° C. for one hour. Cool the reaction mixture to roomtemperature. Dilute the reaction with water (2 L) and extract themixture with EtOAc (3×2 L). Dry the combined organic extracts overanhydrous sodium sulfate, filter and concentrate the filtrate underreduced pressure. Add DCM (2 L) and hexane (2 L) and wash the resultingorganic solution with saturated NaCl (2×1 L). Concentrate the organicsolution under reduced pressure to a minimum volume. Filter off thesolids to give the title compound 180 g (57%). MS (m/z): 359/361(M+1/M+3).

Preparation 152-Bromo-5-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-6,6-dimethyl-thieno[2,3-c]pyrrol-4-one

Treat a suspension of sodium hydride (60 wt % in mineral oil, 3.9 g,97.5 mmol) in DMF (203 mL) at 0° C. with2-bromo-6,6-dimethyl-5H-thieno[2,3-c]pyrrol-4-one (20 g, 81.3 mmol)followed by (2-bromoethoxy)-tert-butyldimethylsilane (23.3 g, 97.5mmol). Stir the reaction at 0° C. for one hour. Remove the ice bath andstir the reaction mixture overnight. Quench the reaction mixture withsaturated aqueous ammonium chloride and extract with EtOAc. Wash theorganic solution with saturated NaCl. Dry the organic solution overanhydrous sodium sulfate, filter and concentrate the filtrate underreduced pressure. Purify the residue by silica gel column chromatographyeluting with 20% EtOAc in hexane to give the title compound 26 g (79%).MS (m/z): 404/406 (M+1/M+3).

The following compound is prepared essentially by the method ofPreparation 15.

Prep. No. Compound Name Structure MS (m/z): 16 2′-Bromo-5′-(2-morpholinoethyl)spiro[cyclopropane- 1,6′-thieno[2,3-c]pyrrole]-4′-one

357/359 (M + 1/M + 3)

2-(2-Chloro-5-methyl-pyrimidin-4-yl)-6,6-dimethyl-5-(2-morpholinoethyl)thieno[2,3-c]pyrrol-4-one

Degas a mixture of2-bromo-6,6-dimethyl-5-(2-morpholinoethyl)thieno[2,3-c]pyrrol-4-one(5.76 g, 16 mmol), bis(pinacolato)diboron (4.88 g, 19.2 mmol) andpotassium acetate (4.86 g, 48 mmol) in 1,4-dioxane (80 mL) with nitrogenfor 20 minutes. Add (1,1′-bis(diphenylphosphino)ferrocene)palladium(II)chloride (668 mg, 0.80 mmol) and heat the mixture at 90° C. overnight.Cool the reaction to room temperature, concentrate the filtrate and thentreat the residue with EtOAc. The precipitate is collected by vacuumfiltration. To the solid (3.7 g) add 2,4-dichloro-5-methylpyrimidine(1.5 g, 9.1 mmol), 1,4-dioxane (50 mL), potassium carbonate (3.8 g, 27mmol) and water (33 mL). Degas the resulting mixture with nitrogen for20 minutes. Add tetrakis(triphenylphosphine)palladium (790 mg, 0.68mmol) and heat the mixture to 90° C. for two hours. Cool the mixture toroom temperature and dilute with EtOAc. Wash the organic solution withsaturated NaCl. Dry the organic solution over anhydrous sodium sulfate,filter and concentrate the filtrate under reduced pressure. Purify theresidue by silica gel column chromatography eluting with a gradient from0-10% MeOH in EtOAc to give the title compound 1.82 g (19%). MS (m/z):407 (M+1).

The following compounds are prepared essentially by the method ofPreparation 17.

Prep. MS No. Compound Name Structure (m/z): 182-(2,5-Dichloropyrimidin-4-yl)-6,6- dimethyl-5-(2-morpholinoethyl)thieno[2,3- c]pyrrol-4-one

427 (M + 1) 19 2-(2-Chloro-5-fluoro-pyrimidin-4- yl)-6,6-dimethyl-5-(2-morpholinoethyl)thieno[2,3- c]pyrrol-4-one

411 (M + 1) 20 2-[2-Chloro-5- (trifluoromethyl)pyrimidin-4-yl]-6,6-dimethyl-5-(2- morpholinoethyl)thieno[2,3- c]pyrrol-4-one

461 (M + 1) 21 5-[2-[tert- Butyl(dimethyl)silyl]oxyethyl]-2-(2-chloropyrimidin-4-yl)-6,6-dimethyl- thieno[2,3-clpyrrol-4-one

438 (M + 1) 22 2-(2-Chloropyrimidin-4-y1)-6,6- dimethyl-5-[2-(5-oxa-8-azaspiro[2.6]nonan-8- yl)ethyllthieno[2,3-clpyrrol-4-one

433 (M + 1) 23 2′-(2-Chloropyrimidin-4-yl)-5′-(2-morpholinoethyl)spiro[cyclopropane- 1,6′-thieno[2,3-c]pyrrole]-4′-one

391 (M + 1)

Preparation 242-(2-Chloropyrimidin-4-yl)-6,6-dimethyl-5-(2-morpholinoethyl)thieno[2,3-c]pyrrol-4-one

Synthetic Method 1:

Degas a mixture of2-bromo-6,6-dimethyl-5-(2-morpholinoethyl)thieno[2,3-c]pyrrol-4-one (200g, 557 mmol), bis(pinacolato)diboron (200 g, 788 mmol) and potassiumacetate (200 g, 2038 mmol) in 1,4-dioxane (1 L) with nitrogen for 15minutes. Add (1,1′-bis(diphenylphosphino)ferrocene)palladium(II)chloride (20 g, 27 mmol) and heat the mixture to 90° C. Heat the mixtureat 90° C. for one hour. Cool the reaction to 50° C. and add potassiumcarbonate (250 g, 1809 mmol), 2,4-dichloropyrimidine (230 g, 1543 mmol)and water (300 mL). Heat the mixture at 90° C. for one hour. Cool themixture to 35° C. and add water (700 mL). Extract the reaction mixturewith DCM (2 L). The aqueous solution was back extracted with DCM (500mL). Dry the combined organic solutions over anhydrous magnesiumsulfate, filter and concentrate the filtrate under reduced pressure.Dilute the residue with 10% EtOAc in hexane (2 L) and stir for one hour.Decant the mother liquor and rinse the solids with hexane (500 mL).Dissolve the solids in DCM (300 mL) and slowly add hexanes (2 L).Collect the resulting solids by vacuum filtration and dry to give thetitle compound 150 g (65%). MS (m/z): 393 (M+1).

Synthetic Method 2:

Cool a mixture of2-(2-chloropyrimidin-4-yl)-6,6-dimethyl-5H-thieno[2,3-c]pyrrol-4-onehydrochloride (10 g, 32 mmol) and tetrabutylammonium iodide (1.17 g,3.16 mmol) in N-methylpyrrolidone (211 mL) to 0° C. using an ice waterbath. Add sodium hydride (60 wt % in mineral oil, 5.06 g, 126.5 mmol) inportions. Stir the mixture at 0° C. for 10 minutes and then add4-(2-bromoethyl)morpholine hydrobromide (13.9 g, 50.6 mmol). Remove theice bath and stir the mixture for four hours. Quench the reactionmixture with saturated aqueous ammonium chloride and dilute the mixturewith water (1 L). Extract the mixture with isopropyl acetate (4×700 mL).Dry the combined organic extracts over anhydrous sodium sulfate, filterand concentrate the filtrate under reduced pressure. Add 20% EtOAc inhexane and stir the mixture for one hour. Collect the solid by vacuumfiltration and dry to give the title compound 8.6 g (69%). MS (m/z): 393(M+1).

Synthetic Method 3:

Treat a solution of2-(2-chloropyrimidin-4-yl)-6,6-dimethyl-5H-thieno[2,3-c]pyrrol-4-one(500 mg, 1.4 mmol) in DMF (14 mL) with sodium hydride (60 wt % inmineral oil, 129 mg, 3.2 mmol). Stir the mixture for 10 minutes and thenadd 4-(2-bromoethyl)morpholine hydrochloride (412 mg, 1.8 mmol). Stirthe reaction mixture at room temperature overnight. Cool the mixture to0° C. and add 4-(2-bromoethyl)morpholine hydrochloride (165 mg, 0.7mmol) followed by sodium hydride (60 wt % in mineral oil, 14 mg, 0.4mmol). Remove the ice bath and stir the mixture at room temperatureovernight. Add sodium hydride (60 wt % in mineral oil, 14 mg, 0.4 mmol)and stir the resulting mixture at room temperature for five hours.Dilute the mixture with water and extract with EtOAc. Wash the organicextracts with 5% aqueous lithium chloride. Concentrate the organicsolution under reduced pressure. Purify the residue by silica gel columnchromatography eluting with a gradient from 0-10% MeOH in DCM to givethe title compound 524 mg (93%). MS (m/z): 393 (M+1).

Preparation 255-[2-[tert-Butyl(dimethyl)silyl]oxyethyl]-6,6-dimethyl-2-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]thieno[2,3-c]pyrrol-4-one

Degas a mixture of5-[2-[tert-butyl(dimethyl)silyl]oxyethy]-2-(2-chloropyrimidin-4-yl)-6,6-dimethyl-thieno[2,3-c]pyrrol-4-one(6 g, 13.7 mmol), 2-methylpyrazol-3-amine (1.60 g, 16.4 mmol), cesiumcarbonate (8.92 g, 27.4 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (790 mg, 1.37 mmol) and1,4-dioxane (150 mL) with nitrogen for 10 minutes. Addpalladium(II)acetate (610 mg, 2.74 mmol) and heat the mixture at 90° C.for 2.5 hours. Cool the mixture to room temperature and stir the mixtureat room temperature overnight. Dilute the reaction mixture with 10% MeOHin DCM and stir the mixture for 15 minutes. Filter the mixture throughCELITE® and wash the solids with 10% MeOH in DCM. Concentrate thefiltrate under reduced pressure. Purify the residue by silica gel columnchromatography eluting with a gradient from 60-100% EtOAc in DCM to givethe title compound 5.73 g (84%). MS (m/z): 499 (M+1).

Preparation 262-Bromo-5-(2-hydroxyethyl)-6,6-dimethyl-thieno[2,3-c]pyrrol-4-one

Treat2-bromo-5-[2-[tert-butyl(dimethyl)siyl]-oxyethyl]-6,6-dimethyl-thieno[2,3-c]pyrrol-4-one(26 g, 64 mmol) in THF (40 mL) with acetic acid (120 mL) and water (40mL). Stir the mixture at room temperature overnight. Concentrate thereaction mixture under reduced pressure. Dilute the residue with EtOAcand wash the resulting solution with saturated aqueous sodiumbicarbonate followed by saturated NaCl. Dry the organic solution overanhydrous sodium sulfate, filter and concentrate the filtrate to givethe title compound 18.97 g (100%). MS (m/z): 290/292 (M+1/M+3).

The following compound is prepared essentially by the method ofPreparation 26.

Prep. MS No. Compound Name Structure Comments (m/z): 275-(2-Hydroxyethyl)-6,6- dimethyl-2-[2-[(2- methylpyrazol-3-yl)aminolpyrimidin-4- yl]thieno[2,3-c]pyrrol-4-one

4N HCl dioxane is used. 385 (M + 1)

Preparation 282-(2-Bromo-6,6-dimethyl-4-oxo-thieno[2,3-c]pyrrol-5-yl)ethylmethanesulfonate

Cool a solution of2-bromo-5-(2-hydroxyethyl)-6,6-dimethyl-thieno[2,3-c]pyrrol-4-one (18.97g, 65.4 mmol) in DCM (300 mL) to 0° C. Treat the mixture withtriethylamine (13.7 mL, 98.1 mmol) and methanesulfonyl chloride (8.24 g,71.9 mmol). Stir the mixture at 0° C. for two hours. Wash the solutionwith water and saturated NaCl. Dry the organic solution over anhydroussodium sulfate, filter and concentrate the filtrate under reducedpressure. Purify the residue by silica gel column chromatography elutingwith EtOAc to give the title compound 23.8 g (99%). MS (m/z): 368/370(M+1/M+3).

The following compound is prepared essentially by the method ofPreparation 28.

Prep. MS No. Compound Name Structure (m/z): 29 2-[6,6-Dimethyl-2-[2-[(2-methylpyrazol-3- yl)amino]pyrimidin-4-yl]-4-oxo-thieno[2,3-c]pyrrol-5-yl]ethyl methanesulfonate

463 (M + 1)

Preparation 30 3-Ethyl-4-nitro-1H-pyrazole

Dissolve 3-ethyl-1H-pyrazole (1 g, 10.4 mmol) in sulfuric acid (5 mL)and cool the mixture to a −5° C. Then add potassium nitrate (1.16 g,11.4 mmol) in portions to the mixture. Stir the mixture overnight whileallowing it to slowly warm to room temperature. Cool the mixture to 0°C. and quench slowly with ammonium hydroxide until the pH isapproximately 10. Collect the resulting solid by vacuum filtration andwash with a small amount of water. Cool the filtrate to 0° C. and thencollect the solid from the filtrate by vacuum filtration and wash with asmall amount of water. Combine the solids and dissolve in DCM. Dry theorganic solution over anhydrous sodium sulfate, filter and concentratethe filtrate under reduced pressure. Co-evaporate once with diethylether to give the title compound 1.34 g (91%). MS (m/z): 140 (M-1).

Preparation 31 tert-Butyl 3-methoxy-4-nitro-pyrazole-1-carboxylate

Treat a suspension of 5-methoxy-4-nitro-1H-pyrazole (3 g, 21 mmol),di-tert-butyl-dicarbonate (6.9 g, 31.6 mmol) and 4-dimethylaminopyridine(1.28 g, 10.5 mmol) in DCM (300 mL) with triethylamine (5.85 mL, 42mmol) and stir the mixture at room temperature overnight. Concentratethe reaction mixture under reduced pressure. Purify the residue bysilica gel column chromatography eluting with a gradient from 1-10%EtOAc in hexane to give the title compound 3.48 g (68%). ¹H NMR (399.8MHz, DMSO-d₆) δ 9.10 (s, 1H), 3.98 (s, 3H), 1.56 (s, 9H).

Preparation 32 3-Ethyl-1H-pyrazol-4-amine

Treat a suspension of palladium (5 wt % on carbon, 450 mg, 0.21 mmol) inEtOH (21 mL) with 3-ethyl-4-nitro-1H-pyrazole (300 mg, 2.13 mmol). Stirthe resulting mixture under a hydrogen atmosphere for 6.5 hours. Filterthe reaction mixture through CELITE® and rinse the solids withadditional EtOH. Concentrate the filtrate under reduced pressure to givethe title compound 240 g (99%). ¹H NMR (400.1 MHz, CD₃CN) δ 7.02 (s,1H), 2.54 (q, J=7 Hz, 3H), 1.17 (t, J=7 Hz, 9H).

The following compound is prepared essentially by the method ofPreparation 32.

Prep. MS No. Compound Name Structure (m/z): 33 tert-Butyl 4-amino-3-methoxy- pyrazole-1- carboxylate

214 (M + 1)

Preparation 34 tert-Butyl N-(2-cyclopropylpyrazol-3-yl)carbamate

Cool a solution of 2-cyclopropylpyrazole-3-carboxylic acid (4 g, 26mmol) in THF (35 mL) to 0° C. and then add triethylamine (5.5 mL, 39mmol) followed by diphenylphosphonic azide (8.5 mL, 39 mmol). Stir themixture for four hours while warm the reaction temperature slowly toroom temperature. Add tert-butyl alcohol (4.99 mL) and heat the mixtureat 70° C. for 18 hours. Concentrate the reaction mixture under reducedpressure. Purify the residue by silica gel column chromatography elutingwith a gradient from 0-20% MeOH in DCM to give the title compound 5.39 g(92%). MS (m/z): 224 (M+1).

Preparation 35 2-Cyclopropylpyrazol-3-amine

Treat a solution of tert-butyl N-(2-cyclopropylpyrazol-3-yl)carbamate(5.39 g, 24 mmol) in DCM (12 mL) with trifluoroacetic acid (16 mL, 213mmol). Stir the solution at room temperature for one hour. Concentratethe reaction mixture under reduced pressure. Dissolve the residue in DCMand treat with saturated aqueous sodium bicarbonate solution until thepH of the aqueous phase persists at >7. Separate the phases and dry theorganic phase over anhydrous sodium sulfate. Filter the mixture andconcentrate the filtrate under reduced pressure. Concentrate the aqueousphase under reduced pressure. Combine the residues from the organic andaqueous phases and purify by reverse phase column chromatography(Column: 130 g C18; Mobile Phase: A) water, B) ACN; Gradient: 0-20% B).Concentrate the fractions and dissolve the residue in 25% MeOH in DCM.Filter the mixture and concentrate the filtrate under reduced pressure.Dissolve the residue in EtOAc and add water. Separate the layers andback extract the aqueous layer with EtOAc (8×100 mL). Concentrate thecombined organic extract under reduced pressure to give the titlecompound 2.27 g (76%). ¹H NMR (400.1 MHz, CD₃CN) δ 7.02 (d, J=2 Hz, 1H),5.33 (d, J=2 Hz, 1H), 4.28 (bs, 2H), 3.10 (m, 1H), 0.96 (m, 4H).

Preparation 36 2-(Dibenzylamino)ethanol

Treat a mixture of 2-(benzylamino)ethanol (0.95 mL, 6.6 mmol) in ACN (35mL) with potassium carbonate (1.83 g, 13.2 mmol) followed by benzylbromide (1.18 mL, 9.89 mmol). Heat the reactions mixture at 80° C. for1.5 hours. Cool the reaction to room temperature and filter the mixture.Concentrate the filtrate under reduced pressure and purify the residueby silica gel column chromatography eluting with a gradient from 0-30%EtOAc in hexane to give the title compound 1.7 g (100%). MS (m/z): 242(M+1).

Preparation 37 2-[2-(Dibenzylamino)ethoxy]-2,2-difluoro-acetic acid

Treat a solution of 2-(dibenzylamino)ethanol (1.5 g, 6.2 mmol) andsodium chloro-2,2-difluoro-acetic acid (950 mg, 6.19 mmol) in THF (12mL) at 0° C. with sodium hydride (60 wt % in mineral oil, 500 mg, 12.5mmol). Heat the reaction mixture to reflux overnight. Add additionalsodium hydride (60 wt % in mineral oil, 120 mg, 3 mmol) to the reactionmixture and continue heating for an additional hour. Cool the reactionto room temperature and dilute with water. Extract the mixture withdiethyl ether. Separate the layers and adjust the aqueous layer to pH 6with 6 N hydrochloric acid. Extract the aqueous solution with EtOAc.Combine all organic solutions and dry over anhydrous sodium sulfate.Filter the mixture and concentrate the filtrate under reduced pressureto give the title compound 1.03 g (49%). MS (m/z): 336 (M+1).

Methyl 2-[2-(dibenzylamino)ethoxy]-2,2-difluoro-acetate

Treat a solution of 2-[2-(dibenzylamino)ethoxy]-2,2-difluoro-acetic acid(100 mg, 0.298 mmol) in toluene (9 mL) and MeOH (2 mL) with(trimethylsilyl)diazomethane (2 M in hexane, 0.16 mL, 0.32 mmol) dropwise. Stir the mixture for 15 minutes at room temperature. Quench thereaction with acetic acid (0.1 mL) and concentrate the reaction mixtureunder reduced pressure to give the title compound 102 mg (98%). MS(m/z): 350 (M+1).

Preparation 39 4-Benzyl-2,2-difluoro-morpholin-3-one

Treat a suspension of palladium (10% on carbon, 50 mg, 0.141 mmol) inEtOH (15 mL) with methyl2-[2-(dibenzylamino)ethoxy]-2,2-difluoro-acetate (485 mg, 1.39 mmol) inEtOH (15 mL). Stir the reaction mixture under a hydrogen atmosphere(balloon) at room temperature overnight. Filter the reaction mixturethrough CELITE® and concentrate the filtrate under reduced pressure togive the title compound 294 mg (93%). MS (m/z): 228 (M+1).

Preparation 40 4-Benzyl-2,2-difluoro-morpholine

Treat a solution of 4-benzyl-2,2-difluoro-morpholin-3-one (290 mg, 1.28mmol) in THF (13 mL) with boron dimethyl sulfide complex (2 M in THF,3.06 mL, 6.12 mmol). Heat the reaction mixture at 55° C. for 3.5 hoursand then remove the heat and continue stirring overnight. Heat thereaction mixture to 55° C. for an additional two hours. Cool thereaction mixture to room temperature and quench by the dropwise additionof hydrochloric acid (6 N, 3.06 mL, 18.4 mmol). Heat the reactionmixture at 100° C. for one hour. Cool the mixture to room temperatureand concentrate under reduced pressure. Dilute the mixture with waterand adjust the pH to 12 with 2 N sodium hydroxide. Extract the mixturewith EtOAc. Dry the organic extracts over anhydrous sodium sulfate,filter and concentrate the filtrate under reduced pressure to give thetitle compound 120 mg (44%). MS (m/z): 214 (M+1).

Preparation 412-Bromo-6,6-dimethyl-5-[2-(5-oxa-8-azaspiro[2.6]nonan-8-yl)ethyl]thieno[2,3-c]pyrrol-4-one

Heat a mixture of2-(2-bromo-6,6-dimethyl-4-oxo-thieno[2,3-c]pyrrol-5-yl)ethylmethanesulfonate (2.76 g, 6.9 mmol) and 5-oxa-8-azaspiro[2.6]nonane(2.18, 16.3 mmol) in DMF (33 mL) at 80° C. overnight. Cool the mixtureto room temperature and dilute with EtOAc. Wash the organic solutionwith saturated NaCl (3×30 mL). Dry the organic solution over anhydroussodium sulfate, filter and concentrate the filtrate under reducedpressure. Purify the residue by reverse phase column chromatography(Column: 100 g Gold C18; Mobile Phase: A) 0.1% formic acid in water, B)0.1% formic acid in ACN; Gradient: 5% B for 5 minutes, 5%-50% B over 20minutes; Flow Rate: 53 mL/minute) to give the title compound 3.6 g(85%). MS (m/z): 399/401 (M+1/M+3).

Preparation 42 tert-Butyl4-[[4-[6,6-dimethyl-5-(2-morpholinoethyl)-4-oxo-thieno[2,3-c]pyrrol-2-yl]-5-methyl-pyrimidin-2-yl]amino]-3-methoxy-pyrazole-1-carboxylate

Degas a mixture of2-(2-chloro-5-methyl-pyrimidin-4-yl)-6,6-dimethyl-5-(2-morpholinoethyl)thieno[2,3-c]pyrrol-4-one(250 mg, 0.61 mmol), tert-butyl 4-amino-3-methoxy-pyrazole-1-carboxylate(157 mg, 0.74 mmol), cesium carbonate (300 mg, 0.92 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (71 mg, 0.12 mmol) and1,4-dioxane (6.4 mL) with nitrogen for 15 minutes. Addpalladium(II)acetate (14 mg, 0.0614 mmol) and heat the mixture at 110°C. overnight. Cool the mixture to room temperature and dilute withEtOAc. Wash the organic solution with saturated NaCl. Dry the organicsolution over anhydrous sodium sulfate, filter and concentrate thefiltrate under reduced pressure. Purify the residue by HPLC on a C18column (Column: 150 g; Mobile Phase: A) 0.10% Formic Acid in Water, B)0.10% Formic Acid in ACN; Gradient: 10-50% B; Flow Rate: 60 mL/min) togive the title compound 101 mg (28%). MS (m/z): 584 (M+1).

The following compounds are prepared essentially by the method ofPreparation 42.

Prep. MS No. Compound Name Structure Comment (m/z): 43 tert-Butyl4-[[4-[6,6- dimethyl-5-(2- morpholinoethyl)-4-oxo-thieno[2,3-c]pyrrol-2- yl]pyrimidin-2-yl]aminol-3- methoxy-pyrazole-1-carboxylate

Catalyst: tris(dibenzylideneacetone) dipalladium (0) 570 (M + 1) 44tert-Butyl 4-[[4-6,6- dimethyl-5-(2- morpholinoethyl)-4-oxo-thieno[2,3-c]pyrrol-2-yl-5- fluoro-pyrimidin-2- yl]amino]-3-methoxy-pyrazole-1-carboxylate

588 (M + 1) 45 tert-Butyl 5-cyclopropyl-4- [[4-[6,6-dimethyl-5-(2-morpholinoethyl)-4-oxo- thieno[2,3-c]pyrrol-2- yl]pyrimidin-2-yl]aminolpyrazole-1- carboxylate

580 (M + 1)

EXAMPLE 16,6-Dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one

Synthetic Method 1:

Slowly add 2-methylpyrazol-3-amine (75 g, 772 mmol) to a suspension ofsodium hydride (60 wt % in mineral oil, 30 g, 750 mmol) inN-methylpyrrolidone (500 mL). Stir the resulting mixture for 90 minutes.Add a solution of2-(2-chloropyrimidin-4-yl)-6,6-dimethyl-5-(2-morpholinoethyl)thieno[2,3-c]pyrrol-4-one(145 g, 369 mmol) in N-methylpyrrolidone (200 mL). Cool the exothermicreaction to room temperature and pour the reaction into water (3 L).Adjust the pH to ˜3 with concentrated hydrochloric acid (200 mL).Extract the mixture with DCM (4×2 L). Neutralize the aqueous layer using5 M sodium hydroxide. Extract this aqueous solution with DCM (2×2 L).Combine these organic extracts and wash with water (2 L). Dry theorganics over anhydrous sodium sulfate, filter and concentrate thefiltrate under reduced pressure. Purify the residue on a silica gel plug(2 kg) eluting successively with DCM (2 L), 2.5% EtOH in DCM (2 L), 5%EtOH in DCM (2 L), 7.5% EtOH in DCM (2 L) and finally 10% EtOH in DCM(10 L). Concentrate the appropriate fractions under reduced pressure.Add EtOAc (1 L) and concentrate under reduced pressure. Add EtOAc (1 L)and concentrate under reduced pressure. Add EtOAc (500 mL) and hexane(500 mL). Collect the solid by vacuum filtration and wash the solid withhexane (500 mL). Dry the solid under vacuum at 50° C. to give the titlecompound 65.7 g (39%). MS (m/z): 454 (M+1).

Synthetic Method 2:

Degas a mixture of2-(2-chloropyrimidin-4-yl)-6,6-dimethyl-5-(2-morpholinoethyl)thieno[2,3-c]pyrrol-4-one(20.8 g, 52.9 mmol), 2-methylpyrazol-3-amine (5.7 g, 58.2 mmol), cesiumcarbonate (37.9 g, 116.5 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.6 g, 4.5 mmol) and1,4-dioxane (529 mL) with nitrogen for 10 minutes. Addtris(dibenzylideneacetone)dipalladium(0) (2.4 g, 2.6 mmol) and heat themixture to 85° C. for four hours. Cool the mixture to room temperatureand filter the mixture through filter paper. Concentrate the filtrateunder reduced pressure. Repeat the reaction starting with 8 g of2-(2-chloropyrimidin-4-yl)-6,6-dimethyl-5-(2-morpholinoethyl)thieno[2,3-c]pyrrol-4-oneand combine the two residues. Purify the residue by silica gel columnchromatography (330 g) eluting with a gradient from 5-25% MeOH in (10%EtOAc in DCM). Pool the fractions and concentrate under reducedpressure. Re-purify the residue by silica gel column chromatography (330g) eluting with a gradient from 5-25% MeOH in 10% EtOAc in DCM. Pool thefractions and concentrate under reduced pressure. Dissolve the residuein DCM (400 mL) and then add acetone (1 L). Slowly concentrate themixture under reduced pressure to approximately 700 mL. Collect thesolid by vacuum filtration to give the title compound 14.8 g (48%). MS(m/z): 454 (M+1).

Synthetic Method 3:

Degas a mixture of2-(2-chloropyrimidin-4-yl)-6,6-dimethyl-5-(2-morpholinoethyl)thieno[2,3-c]pyrrol-4-one(250 mg, 0.64 mmol), 2-methylpyrazol-3-amine (124 mg, 1.3 mmol), cesiumcarbonate (622 mg, 1.9 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (55 mg, 0.095 mmol) and1,4-dioxane (6.4 mL) with nitrogen for 15 minutes. Addpalladium(II)acetate (14.3 mg, 0.0636 mmol) and heat the mixture at 90°C. overnight. Cool the mixture to room temperature and filter themixture through filter paper. Wash the solids with 10% MeOH in DCM.Concentrate the filtrate under reduced pressure. Repeat the reaction andcombine the two residues. Purify the residue by HPLC on a C18 column(30×75 mm, 5 um, xbridge ODB) eluting with a 85 mL/minute gradient from9-28% ACN in 10 mM ammonium carbonate (pH 10) in water. Pool thefractions and concentrate under reduced pressure to remove the ACN.Lyophilize the aqueous solution to give the title compound 100 mg (18%).MS (m/z): 454 (M+1).

The following compounds are prepared essentially by the synthetic method3 of Example 1.

Physical data Ex. MS No. Chemical name Structure (m/z):  26,6-Dimethyl-2-{5- methyl-2-[(1-methyl- 1H-pyrazol-5-yl)amino]pyrimidin-4- yl}-5-[2-(morpholin- 4-yl)ethyl]-5,6- dihydro-4H-thieno [2,3-c]pyrrol-4- one

468 (M + 1)  3 4-[(4-{6,6-Dimethyl- 5-[2-(morpholin-4- yl)ethyl]-4-oxo-5,6- dihydro-4H- thieno[2,3-c]pyrrol-2- yl}pyrimidin-2-yl)amino]-1-methyl- 1H-pyrazole-3- carbonitrile

479 (M + 1)  4 6,6-Dimethyl-2- {2- [(1-methyl-1H- pyrazol-5-yl)amino]pyrimidin-4- yl)-5-[2-(5-oxa-8- azaspiro[2.6]non-8-yl)ethyl]-5,6-dihydro- 4H-thieno [2,3- c]pyrrol-4-one

494 (M + 1)  5 2′-{2-[(1-Methyl-1H- pyrazol-5- yl)amino]pyrimidin-4-yl}-5′-[2-(morpholin-4- yl)ethyl]spiro[cyclopropane- 1,6′-thieno [2,3-c]pyrrol]-4′(5′H)-one

452 (M + 1)  6 6,6-Dimethyl-2-{2- [(1-methyl-1H- pyrazol-5-yl)amino]-5-(trifluoromethyl)pyrimidin- 4-yl}-5-[2- (morpholin-4-yl)ethyl]-5,6-dihydro- 4H-thieno [2,3- c]pyrrol-4-one

522 (M + 1)  7 2-{2-[(3-Methoxy-1- methyl-1H-pyrazol-4- yl)amino]-5-methylpyrimidin-4- yl}-6,6-dimethyl-5-[2- (morpholin-4-yl)ethyl]-5,6-dihydro- 4H-thieno [2,3- c]pyrrol-4-one

498 (M + 1)  8 2-{2-[(2,3- Dimethylpyridin-4- yl)amino]pyrimidin-4-yl}-6,6-dimethyl-5-[2- (morpholin-4- yl)ethyl]-5,6-dihydro- 4H-thieno[2,3- c]pyrrol-4-one

479 (M + 1)  9 6,6-Dimethyl-2-{2- [(1-methyl-1H- pyrazol-4-yl)amino]pyrimidin-4- yl-5-[2-(morpholin- 4-yl)ethyl]-5,6- dihydro-4H-thieno [2,3-c]pyrrol-4- one

454 (M + 1) 10 2-{2-[(4-Fluoro-2- methylphenyl)amino]-5-methylpyrimidin-4- yl}-6,6-dimethyl-5-[2- (morpholin-4-yl)ethyl]-5,6-dihydro- 4H-thieno[2,3- c]pyrrol-4-one

496 (M + 1) 11 6,6-Dimethyl-2-[5- methyl -2-(pyrimidin-4-ylamino)pyrimidin- 4-yl]-5-[2-(morpholin- 4-yl)ethyl]-5,6- dihydro-4H-thieno[2,3-c]pyrrol-4- one

466 (M + 1) 12 2-{2-[(2,3- Dimethylpyridin-4- yl)amino] -5-methylpyrimidin-4- yl}-6,6-dimethyl-5-[2- (morpholin-4-yl)ethyl]-5,6-dihydro- 4H-thieno [2,3- c]pyrrol-4-one

493 (M + 1) 13 4- [(4-{6,6-Dimethyl- 5-[2-(morpholin-4-yl)ethyl]-4-oxo-5,6- dihydro-4H- thieno[2,3-c]pyrrol-2- yl}pyrimidin-2-yl)amino]pyridine-3- carbonitrile

476 (M + 1) 14 2-{5-Chloro-2-[(1- methyl-1H-pyrazol-5-yl)amino]pyrimidin-4- yl}-6,6-dimethyl-5-[2- (morpholin-4-yl)ethyl]-5,6-dihydro- 4H-thieno[2,3- c]pyrrol-4-one

488 (M + 1) 15 2-{5-Fluoro-2-[(1- methyl-1H-pyrazol-5-yl)amino]pyrimidin-4- yl}-6,6-dimethyl-5-[2- (morpholin-4-yl)ethyl]-5,6-dihydro- 4H-thieno[2,3- c]pyrrol-4-one

472 (M + 1) 16 4- [(4-{6,6-Dimethyl- 5-[2-(morpholin-4-yl)ethyl]-4-oxo-5,6- dihydro-4H- thieno[2,3-c]pyrrol-2-yl}-5-fluoropyrimidin- 2-yl)amino]-1-methyl- 1H-pyrazole-3- carbonitrile

497 (M + 1) 17* 2-{2- [(1,3-Dimethyl- 1H-pyrazol-5-yl)amino]pyrimidin-4- yl}-6,6-dimethyl-5-[2- (morpholin-4-yl)ethyl]-5,6-dihydro- 4H-thieno[2,3- c]pyrrol-4-one

468 (M + 1) 18 2-{2-[(2,4- Difluorophenyl)amino]- 5-methylpyrimidin-4-yl}-6,6-dimethyl-5- [2-(morpholin-4- yl)ethyl]-5,6-dihydro-4H-thieno[2,3- c]pyrrol-4-one

500 (M + 1) 19 2-{2-[(2,4- Difluorophenyl)amino] pyrimidin-4-yl}-6,6-dimethyl-5-[2- (morpholin-4- yl)ethyl]-5,6-dihydro- 4H-thieno[2,3-c]pyrrol-4-one

486 (M + 1) *Use[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate as ligand.

EXAMPLE 204-[(4-{6,6-Dimethyl-5-[2-(morpholin-4-yl)ethyl]-4-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl}pyrimidin-2-yl)amino]-1H-pyrazole-5-carbonitrile

Heat a solution of2-(2-chloropyrimidin-4-yl)-6,6-dimethyl-5-(2-morpholinoethyl)thieno[2,3-c]pyrrol-4-one(350 mg, 0.89 mmol), 4-amino-1H-pyrazole-5-carbonitrile (116 mg, 1.07mmol), potassium carbonate (320 mg, 2.32 mmol),2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl(87 mg, 0.18 mmol), tert-butyl alcohol (2.3 mL) and acetic acid (onedrop) at 90° C. for two hours. Cool the mixture to room temperature.Dilute the mixture with 10% MeOH in DCM and filter the solution througha CELITE® column with a small amount of silica gel on top. Wash thecolumn with 10% MeOH in DCM and concentrate the filtrate under reducedpressure. Purify the residue by reverse phase column chromatography(Column: C18, 275 g Gold; Mobile Phase: A) 10 mM Ammonium bicarbonate inwater with 5% MeOH, B) ACN; Gradient: 10% B for 5 minutes, gradient to40% B over 25 minutes; Flow Rate: 125 mL/min) to give the title compound240 mg (58%). MS (m/z): 465 (M+1).

The following compound is prepared essentially by the method of Example20.

Physical data Ex. MS No. Chemical name Structure (m/z): 216,6-Dimethy1-5-[2- (morpholin-4- yl)ethyl]-2-[2-(1H- 1,2,3-triazol-5-4-yl]-5,6-dihydro- 4H-thieno[2,3- c]pyrrol-4-one

441 (M + 1)

EXAMPLE 226,6-Dimethyl-2-{2-[(5-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one

Purge a mixture of2-(2-chloropyrimidin-4-yl)-6,6-dimethyl-5-(2-morpholinoethyl)thieno[2,3-c]pyrrol-4-one(230 mg, 0.59 mmol), 3-methyl-1H-pyrazol-4-amine (142 mg, 0.73 mmol),chloro[2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II)(8 mg, 0.012 mmol),2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (5 mg, 0.012mmol) and sodium tert-butoxide (118 mg, 1.2 mmol) three times withnitrogen. Add tert-butyl alcohol (2 mL), seal the reaction and stir themixture at room temperature for 1.5 hours. Treat the reaction mixturewith EtOAc and stir the mixture overnight. Concentrate under reducedpressure. Dissolve the residue in EtOAc and wash the organic solutionwith saturated aqueous ammonium chloride. Back extract the aqueous layertwice with EtOAc. Dry the combine organic extracts over anhydrous sodiumsulfate, filter and concentrate the filtrate under reduced pressure.Purify the residue by silica gel column chromatography eluting with agradient from 0-10% MeOH in DCM to give the title compound 164 mg (62%).MS (m/z): 454 (M+1).

The following compounds are prepared essentially by the method ofExample 22.

Physical data Ex. MS No. Chemical name Structure (m/z): 23 2-{2-[(1-Cyclopropyl- 1H-pyrazol-5- yl)amino]pyrimidin-4- yl}-6,6-dimethyl-5-[2- (morpholin-4- yl}ethyl]-5,6-dihydro- 4H-thieno[2,3- c]pyrrol-4-one

480 (M + 1) 24 2-{2-[(5-Ethyl-1H- pyrazol-4- yl)amino]pyrimidin-4-yl}-6,6-dimethyl-5-[2- (morpholin-4- yl)ethyl]-5,6-dihydro-4H-thieno[2,3- c]pyrrol-4-one

468 (M + 1)

EXAMPLE 256,6-Dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(thiomorpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one

Heat a mixture of2-[6,6-dimethyl-2-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-4-oxo-thieno[2,3-c]pyrrol-5-yl]ethylmethanesulfonate (260 mg, 0.56 mmol), thiomorpholine (116 mg, 1.12 mmol)and triethylamine (0.18 mL, 0.38 mmol) in ACN (2 mL) at 60° C.overnight. Cool the mixture to room temperature and filter the solutionthrough CELITE®. Wash the solids with 10% MeOH in DCM and concentratethe filtrate under reduced pressure. Purify the residue by reverse phasecolumn chromatography (Column: C18, 275 g Gold; Mobile Phase: A) 10 mMAmmonia in 5% MeOH in water, B) ACN; Gradient: 10% B for 5 minutes,gradient to 10-65% B over 25 mins; Flow Rate: 200 mL/min) to give thetitle compound 170 mg (64%). MS (m/z): 470 (M+1).

The following compounds are prepared essentially by the method ofExample 25.

Physical data Ex. MS No. Chemical name Structure (m/z): 266,6-Dimethyl-2-{2- [(1-methyl-1H- pyrazol-5- yl)amino]pyrimidin-4-yl}-5-[2-(2,2,6,6- tetrafluoromorpholin- 4-yl)ethyl]-5,6- dihydro-4H-thieno [2,3-c]pyrrol-4- one

526 (M + 1) 27 6,6-Dimethyl-2-{2- [(1-methyl-1H- pyrazol-5-yl)amino]pyrimidin- 4-yl}-5-[2-(1,4- oxazepan-4-yl)ethyl]-5,6-dihydro-4H- thieno [2,3-c]pyrrol-4- one

468 (M + 1) 28 6,6-Dimethyl-2-{2- [(1-methyl-1H- pyrazol-5-yl]amino]pyrimidin- 4-yl}-5-[2-(8-oxa-3- azabicyclo[3.2.1]oct-3-yl)ethyl]-5,6- dihydro-4H- thieno [2,3-c]pyrrol-4- one

480 (M + 1) 29 5-[2-(3,3- Difluoropyrrolidin-1- yl)ethyl]-6,6-dimethyl-2-{2- [(1- methyl-1H-pyrazol-5- yl)aminolpyrimidin-4-yl}-5,6-dihydro- 4H-thieno [2,3- c]pyrrol-4-one

474 (M + 1) 30 6,6-Dimethyl-2-{2- [(1-methyl-1H- pyrazol-5-yl)amino]pyrimidin- 4-yl}-5-[2-(2-oxa-5- azabicyclo[4.1.0]hept-5-yl)ethyl]-5,6- dihydro-4H- thieno[2,3 -c]pyrrol-4- one

466 (M + 1) 31 6,6-Dimethyl-5-{2- [(3R)-3- methylmorpholin-4-yl]ethyl}-2-{2-[(1- methyl-1H-pyrazol-5- yl)amino]pyrimidin-4-yl}-5,6-dihydro- 4H-thieno[2,3- c]pyrrol-4-one

468 (M + 1)

EXAMPLE 325-[2-(2,2-Difluoromorpholin-4-yl)ethyl]-6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one

Treat a suspension of palladium hydroxide (20% on carbon, 63 mg, 0.09mmol) in EtOAc (5 mL) with 4-benzyl-2,2-difluoro-morpholine (95 mg, 0.45mmol) in EtOAc (5 mL). Stir the reaction mixture under a hydrogenatmosphere (balloon) at room temperature for five hours. Filter thereaction mixture through CELITE® and isolate the filtrate. To thefiltrate, add triethylamine (0.11 mL, 0.79 mmol) and2-[6,6-dimethyl-2-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-4-oxo-thieno[2,3-c]pyrrol-5-yl]ethylmethanesulfonate (306 mg, 0.66 mmol). Heat the mixture at 80° C. for onehour. Add ACN (15 mL) and heat the mixture at 80° C. for two days. Coolthe reaction mixture to room temperature and concentrate under reducedpressure. Purify the residue by silica gel column chromatography elutingwith a gradient from 0-10% MeOH in EtOAc. Concentrate the fractionsunder reduced pressure. Re-purify the residue by silica gel columnchromatography eluting with a gradient from 50-100% EtOAc in hexanefollowed by a second gradient from 0-10% MeOH in EtOAc to give the titlecompound 47 mg (30%). MS (m/z): 490 (M+1).

EXAMPLE 335-[2-(6,6-Difluoro-1,4-oxazepan-4-yl)ethyl]-6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one

Treat 6,6-difluoro-1,4-oxazepane hydrochloride (200 mg, 0.15 mmol) withcarbonate resin (3 molar equivalents) in DCM (5 mL). Rotate the resinsuspension for one hour. Remove the solids by filtration and treat thefiltrate with p-toluenesulfonic acid (250 mg, 1.45 mmol). Stir theresulting mixture for two hours and then concentrate the mixture underreduced pressure. Add ACN (2 mL) and2-[6,6-dimethyl-2-{2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl}-4-oxo-thieno[2,3-c]pyrrol-5-yl]ethylmethanesulfonate (200 mg, 0.43 mmol). Treat the resulting solution withtriethylamine (0.15 mL, 1.08 mmol). Seal the reaction vessel and heatthe mixture at 80° C. for three hours. Cool to room temperature andconcentrate the reaction mixture. Purify the residue by reverse phasecolumn chromatography (Column: 50 g C-18; Mobile Phase: A) 0.1% TFA inwater, B) 0.1% TFA in ACN; Gradient 10-80% B). Concentrate the fractionscontaining product. Dissolve the residue in DCM and wash with saturatedaqueous sodium bicarbonate solution. Dry the organic solution overanhydrous sodium sulfate, filter and concentrate the filtrate underreduced pressure. Purify the residue by reverse phase columnchromatography (Column: 15 g Gold C-18; Mobile Phase: A) 10 mM ammoniumcarbonate in water with 10% MeOH, B) ACN; Gradient 10-80% B) to give thetitle compound 16 mg (7%). MS (m/z): 504 (M+1).

EXAMPLE 345-{2-[Cyclopropyl(methyl)amino]ethyl}-6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one

Heat a solution of2-[6,6-dimethyl-2-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-4-oxo-thieno[2,3-c]pyrrol-5-yl]ethylmethanesulfonate (70 mg, 0.16 mmol) and N-methylcyclopropanamine (77 mg,1.08 mmol) in DMF (1.7 mL) at 90° C. overnight. Cool the mixture to roomtemperature. Purify the solution by reverse phase column chromatography(Column: 100 g Gold C-18; Mobile Phase: A) 0.1% formic acid in water, B)0.1% formic acid ACN; Gradient: 5% B for 5 minutes, gradient to 65% Bover 25 minutes; Flow Rate: 60 mL/min) to give the title compound 70 mg(37%). MS (m/z): 438 (M+1).

The following compound is prepared essentially by the method of Example34.

Physical data Ex. MS No. Chemical name Structure (m/z): 356,6-Dimethyl-2-{2- [(1-methyl-1H- pyrazol-5- yl)amino]pyrimidin-4-yl}-5-[2-(7-oxa-4- azaspiro[2.5]oct-4- yl)ethyl]-5,6-dihydro-4H-thieno[2,3- c]pyrrol-4-one

480 (M + 1)

EXAMPLE 362-{2-[(3-Methoxy-1H-pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}-6,6-dimethyl-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-onehydrochloride

Stir a solution of tert-butyl4-[[4-[6,6-dimethyl-5-(2-morpholinoethyl)-4-oxo-thieno[2,3-c]pyrrol-2-yl]-5-methyl-pyrimidin-2-yl]amino]-3-methoxy-pyrazole-1-carboxylate(101 mg, 0.173 mmol) and hydrogen chloride (4.0 M in 1,4-dioxane, 2 mL,8 mmol) in MeOH (20 mL) at room temperature for 12 hours. Concentratethe mixture to dryness to give the title compound 80 mg (89%). MS (m/z):484 (M+1).

The following compounds are prepared essentially by the method ofExample 36.

Physical data Ex. MS No. Chemical name Structure (m/z): 37*2-{2-[(3-Methoxy- 1H-pyrazol-4- yl)amino]pyrimidin- 4-yl}-6,6-dimethyl-5-[2-(morpholin-4- yl)ethyl-5,6- dihydro-4H- thieno[2,3-clpyrrol- 4-one

470 (M + 1) 38 2-{2-[(5- Cyclopropyl-1H- pyrazol-4- yl)amino]pyrimidin-4-yl]-6,6-dimethyl- 5-[2-(morpholin-4- yl)ethyl]-5,6- dihydro-4H-thieno[2,3-c]pyrrol- 4-one hydrochloride

480 (M + 1) 39 2- {5-Fluoro-2-[(3- methoxy-1H- pyrazol-4-yl)amino]pyrimidin- 4-yl}-6,6-dimethyl- 5-[2-(morpholin-4-yl)ethyl]-5,6- dihydro-4H- thieno[2,3-c]pyrrol- 4-one hydrochloride

488 (M + 1) *Free base prepared after reaction

EXAMPLE 406,6-Dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-{2-[2-oxa-5-azabicyclo[4.1.0]hept-5-yl]ethyl}-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one,isomer 2

Purify6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one(Example 30) by chiral column chromatography (Column: Lux Cellulose-421.2×250 mm; Mobile Phase: 40% isopropyl alcohol (0.2%isopropylamine)/CO₂); Elution Time: 11 minutes) to give the titlecompound 24 mg (34%). MS (m/z): 466 (M+1).

X-Ray Powder Diffraction

The XRD patterns of crystalline solids are obtained on a Bruker D4Endeavor X-ray powder diffractometer, equipped with a CuKa sourceλ=1.54060 Å) and a Vantec detector, operating at 35 kV and 50 mA. Thesample is scanned between 4 and 40° in 20, with a step size of 0.009° in20 and a scan rate of 0.5 seconds/step, and with 0.6 mm divergence, 5.28fixed anti-scatter, and 9.5 mm detector slits. The dry powder is packedon a quartz sample holder and a smooth surface is obtained using a glassslide. The crystal form diffraction patterns are collected at ambienttemperature and relative humidity. It is well known in thecrystallography art that, for any given crystal form, the relativeintensities of the diffraction peaks may vary due to preferredorientation resulting from factors such as crystal morphology and habit.Where the effects of preferred orientation are present, peak intensitiesare altered, but the characteristic peak positions of the polymorph areunchanged. Furthermore, it is also well known in the crystallography artthat for any given crystal form the angular peak positions may varyslightly. For example, peak positions can shift due to a variation inthe temperature or humidity at which a sample is analyzed, sampledisplacement, or the presence or absence of an internal standard. In thepresent case, a peak position variability of ±0.2 in 20 will take intoaccount these potential variations without hindering the unequivocalidentification of the indicated crystal form. Confirmation of a crystalform may be made based on any unique combination of distinguishing peaks(in units of ° 20), typically the more prominent peaks. The crystal formdiffraction patterns, collected at ambient temperature and relativehumidity, are adjusted based on NIST 675 standard peaks at 8.853 and26.774 degrees 2-theta.

X-Ray Powder Diffraction of Example 1, Crystalline Form 16,6-Dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one(Crystalline Form 1)

Add6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one(103 mg) to a solution of ACN (1 mL) and water (1 mL) and heat themixture at 70° C. for 10 minutes. Filter and allow the solution to coolto room temperature overnight. Add water (2 mL) slowly to the solutionover the course of five hours. Collect the solids by vacuum filtrationand wash with water. Air dry the solids to give the title compound 94 mg(92%).

A prepared sample of Example 1 Crystalline Form 1 is characterized by anXRD pattern using CuKa radiation as having diffraction peaks (2-thetavalues) as described in Table 1 below, and in particular having peaks at19.3 degree in combination with one or more of the peaks selected fromthe group consisting of 15.5, 17.1, 18.0, 20.2, 21.5 and 22.1 degree;with a tolerance for the diffraction angles of 0.2 degrees.

TABLE 1 X-ray powder diffraction peaks of Example 1 Crystalline Form 1Angle Relative Intensity (°2-Theta) (% of most Peak +/− 0.2 intensepeak) 1 7.1 7 2 8.8 11 3 12.6 7 4 14.3 6 5 15.5 29 6 16.6 15 7 17.1 25 817.6 8 9 18.0 63 10 18.7 13 11 19.3 100 12 20.2 24 13 20.7 14 14 21.5 2715 22.1 26 16 22.8 9 17 23.8 13 18 24.5 10 19 26.4 15 20 27.2 13 21 28.09 22 29.3 8

Several lines of evidence indicate that processes involved in tumorinitiation, growth and progression are mediated by activation of one ormore signaling pathways in cancer cells. The mitogen-activated proteinkinase (MAPK) pathway is a key regulator of cellular proliferation andsurvival. ERK is a downstream member of this pathway and plays a centralrole in transmitting extracellular signals from activated receptortyrosine kinases (RTKs) such as EGFR, FGFR, PDGFR, VEGFR etc. Thispathway is a three tiered kinase cascade consisting of the RAF, MEK andERK (extracellular signal regulated kinase) kinases and the activationof this pathway begins with activation of RAS, a small GTPase.Activation of RAS leads to the recruitment of RAF, a serine/threoninekinase and its activation. Activated RAF then phosphorylates andactivates MEK1/2, which in turn phosphorylates and activates ERK1/2.When activated, ERK1/2 phosphorylates several downstream cytoplasmic andnuclear targets involved in cell proliferation, growth, survival and EMT(epithelial-to-mesenchymal transition).

The RAS/MAPK pathway is one of the most important pathways for cellproliferation and it is believed that this pathway is frequentlyactivated in ˜30% of all human cancers. Constitutive MAPK pathwayactivation can result from activating mutations in RAS, BRAF, MEK1, lossof the tumor suppressor NF1 or upstream activation mediated bymutations, amplifications or ligand mediated activation of RTKs. Allthree RAS family genes (KRAS, NRAS and HRAS) have been shown to besomatically mutated in several cancers including colorectal, melanoma,lung and pancreatic cancer, most commonly as a result of single pointmutations at codons 12, 13, and 61. These mutations cause constitutiveactivation of RAS which is accompanied by increased ERK1/2 activity andgrowth signaling. Mutations in codons 12, 13 and 61 of KRAS conferresistance to compounds and monoclonal antibodies inhibiting EGFR. KRASmutations are found in 30% of lung cancers, 90% of pancreatic cancers,10% of gastric cancers and 50% of colorectal cancers. NRAS mutationswere detected in about 10-25% of melanoma. In addition, RAS mutations(HRAS, KRAS, and NRAS) have been identified in ˜55-60% of thyroidcancers. Somatic point mutations in BRAF occur in about 8% of humantumors, most frequently in melanoma (60%), colorectal (10%) and thyroidcancers (50%). In melanoma, all BRAF mutations appear to be withinkinase domain and a single substitution (T→A, V600E) accounts for 80% ofthe mutations. BRAF mutations are found, with rare exceptions, in amutually exclusive pattern with RAS mutations, suggesting that thesegenetic alterations activate common downstream effectors.

Biological Assays

The following assays demonstrate that the exemplified compounds of thepresent invention are inhibitors of ERK1 and ERK2 kinase activity. Theresults of the following assays also demonstrate that the exemplifiedcompounds of the present invention inhibit ERK signaling in cancercells. Additionally, the compound of Example 1 demonstrates ERK pathwaytarget inhibition in certain xenograft tumor models of cancer.Furthermore, the compound of Example 1 inhibits tumor growth in certainxenograft tumor models of cancer.

ERK1 Kinase Assay

The purpose of this assay is to measure the ability of compounds toinhibit ERK1 kinase activity. Perform the ERK1 kinase assay in vitrousing a TR-FRET assay. Start reactions (12.5 μL) by adding 5 μL of ERK1enzyme (Invitrogen, #PR5254B, final concentration 100 ng/mL) plussubstrate GFP-ATF2 (Invitrogen, #PV4445, final concentration 0.2 μM), 5μL of ATP solution (Invitrogen, #PV3227, final concentration 10 μM)prepared in kinase buffer (50 mM Hepes pH 7.4, 5 mM MgCl₂, 0.1 mM EGTA,0.01% Triton X-100, 1 mM DTT) and 2.5 μL of testing compounds in DMSOsolution (final 4%, v/v) in a 384-well PROXIPLATE™ (Perkin Elmer,#GRN6260). Incubate the reaction mixture at room temperature for 60minutes. Stop the reaction by addition of 12.5 μL of stop buffer (10 mMEDTA, 2 nM Tb-anti-pATF2 (pThr71) antibody, Invitrogen, #PV4448) inTR-FRET dilution buffer (Invitrogen, #PV3574). Incubate the plates atroom temperature for an additional 60 minutes and read on an ENVISION®(PerkinElmer) plate reader at the excitation wavelength 340 nm Calculatethe TR-FRET ratio by dividing the GFP acceptor emission signal (at 520nm) by the Tb donor emission signal (at 495 nm). Calculate percentinhibition using compound treated wells relative to on-plate Max (DMSOcontrol) and Min (No enzyme added) control wells TR-FRET ratio data {%inhibition=100−[(test compound−median Min)/(median Max−medianMin)×100]}. Test all compounds at 10 concentrations (20 μM to 0.001 μM)using a 1:3 dilution scheme. Derive Abs_IC₅₀ values by fitting percentinhibition and ten-point concentration data to a 4-parameter nonlinearlogistic equation (equation 205) using ACTIVITYBASE® 7.3 (ID BusinessSolutions Limited).

The exemplified compounds within the scope of the invention are testedin this assay substantially as described above. The results of thisassay demonstrate that all of the exemplified compounds inhibit ERK1kinase activity, with IC₅₀ values less than 0.15 μM. For example, thecompound of Example 1 has an IC₅₀ value of 4.86 nM (±0.20, n=7).

ERK2 Kinase Assay

The purpose of this assay is to measure the ability of compounds toinhibit ERK2 kinase activity. Perform the ERK2 kinase assay in vitrousing a TR-FRET assay. Start all reactions (12.5 μL) by adding 5 μL ofERK2 enzyme (Invitrogen, #PV3595B, final conc 50 ng/mL) plus substrateGFP-ATF2 (Invitrogen, #PV4445, final conc 0.2 μM), 5 μL of ATP solution(Invitrogen, #PV3227, final conc 10 μM) prepared in kinase buffer (50 mMHepes pH 7.4, 5 mM MgCl₂, 0.1 mM EGTA, 0.01% Triton X-100, 1 mM DTT) and2.5 μL of testing compounds in DMSO solution (final 4%, v/v) in a384-well PROXIPLATE™ (Perkin Elmer, #GRN6260). Incubate reactions atroom temperature for 60 minutes. Stop reactions by addition of 12.5 μLof stop buffer (10 mM EDTA, 2 nM Tb-anti-pATF2 (pThr71) antibody,Invitrogen, #PV4448) in TR-FRET dilution buffer (Invitrogen, #PV3574).Incubate the plates at room temperature for an additional 60 minutes andread ON ENVISION® (PerkinElmer) plate reader at the excitationwavelength of 340 nm Calculate a TR-FRET ratio by dividing the GFPacceptor emission signal (at 520 nm) by the Tb donor emission signal (at495 nm). Calculate percent inhibition using compound wells relative toon-plate Max (DMSO control) and Min (No enzyme added) control wellsTR-FRET ratio data {% inhibition=100−[(test compound−median Min)/(medianMax−median Min)×100]}. Test all compounds at 10 concentrations (20 μM to0.001 μM) using a 1:3 dilution scheme. Derive Abs_IC50 values by fittingpercent inhibition and ten-point concentration data to a 4-parameternonlinear logistic equation (equation 205) using ACTIVITYBASE 7.3 (IDBusiness Solutions Limited).

The exemplified compounds within the scope of the invention are testedin this assay substantially as described above. The results of thisassay demonstrate that all of the exemplified compounds inhibit ERK2kinase activity, with IC₅₀ values less than 0.15 μM. For example, thecompound of Example 1 has an IC₅₀ value of 5.24 nM (±0.24, n=7).

ERK1/2 Cell Mechanistic Assay (pRSK1 Alphascreen Assay)

The purpose of this assay is to measure the ability of compounds toinhibit ERK signaling in cancer cells in vitro. Carry out the pRSK1Alphascreen assay using the HCT116 colorectal cancer cell line (ATCC,#CCL-247). Routinely culture HCT116 cells in Dulbecco's Modified Eagle'sMedium (DMEM) (Hyclone, #SH30022) growth medium containing 5% FetalBovine Serum (FBS) (Gibco, #16000-044) in T-150 flasks and incubate in a5% CO₂ incubator at 37° C. Harvest cells when they become confluent andfreeze in freezing medium at 1×10e⁷ cells/mL as “assay ready frozencells” and store in liquid nitrogen. To run the assay, plate 40,000HCT116 cells/well in a 96-well tissue culture plate and incubate at 37°C. in a 5% CO₂ incubator overnight. Test compounds at 10 concentrationsstarting at a 20 μM top concentration and utilize a 1:3 dilution scheme(20 μM to 0.001 μM) with a final DMSO concentration of 0.5% (v/v). Addcompounds in 20 μL serum free growth medium and incubate at 37° C. fortwo hours. Remove growth medium and add 50 μL of 1× lysis buffer [CellSignaling Technology, #9803] containing 1× holt protease and phosphateinhibitor cocktail [Thermo, #78441] to each well and incubate at roomtemperature for 10 minutes on a shaker. Transfer 4 μL of cell lysatefrom each well to respective wells in a 384 well assay plate [PerkinElmer, #6006280] and add 5 μL of reaction mix [2000 parts 1× assaybuffer (Perkin Elmer, #A1000), 1 part biotin-RSK1 antibody (Santa Cruz,#sc-231-B-G), 4 parts pRSK1 antibody (Abcam, #ab32413), 35 partsacceptor beads (Perkin Elmer, #6760617R)]. Seal the plate with foilplate seal (Beckman Coulter, #538619) and incubate at room temperaturefor two hours. Add 2 μL of donor beads [20 parts 1× assay buffer, 1 partdonor beads] to each well and seal the plate with clear plate seal(Applied Biosystems, #4311971) and incubate at room temperature in thedark for two hours. Measure the fluorescence intensity in each well byreading the plates in ENVISION® (PerkinElmer) plate reader. Derive theRel IC₅₀ values by fitting percent pRSK1 inhibition [%inhibition=100−[(test compound−median Min)/(median Max-median Min)×100]and ten-point concentration data to a 4-parameter nonlinear logisticequation (Abase equation 205) using ACTIVITYBASE® 7.3 (ID BusinessSolutions Limited).

The exemplified compounds within the scope of the invention are testedin this assay substantially as described above. The results of thisassay demonstrate that all of the exemplified compounds inhibit ERKsubstrate (RSK) phosphorylation in tumor cells, with IC₅₀ values lessthan 3 μM. For example, the compound of Example 1 has an IC₅₀ value of0.429 μM (±0.173, n=8).

In Vivo Target Inhibition (IVTI) Assay (pRSK1 ELISA Assay)

The purpose of this assay is to measure the ability of a test compoundto inhibit ERK1/2 substrate phosphorylation in an animal model Implantfemale athymic nude mice (22-25 g) from Harlan Laboratories with 5×10e⁶HCT116 colorectal cancer cells (ATCC, #CCL-247) subcutaneously in theright flank region in 200 μL of 1:1 Hank's Balanced Salt Solution(HBSS)+Matrigel solution. Measure tumor growth and body weight twice perweek beginning the seventh day after the implantation. When tumor sizesreach 300-500 mm³, randomize animals and group into groups of fiveanimals. Dose animals with either compound at an appropriate dose in acompound specific vehicle or vehicle alone (vehicle: 1% HEC/0.25% Tween80/0.05% Antifoam) orally and collect tumors and blood at desired timeintervals after dosing. Sacrifice animals using isoflurane anesthesiaplus cervical dislocation. Flash freeze tumors and store at −80° C.until processing for pRSK1 levels by ELISA assay. Collect blood in EDTAtubes and spin down for plasma and freeze at −80° C. in a 96-well plate.Determine compound exposures using standard methods.

Pulverize tumors in liquid nitrogen and lyse in 1× lysis buffer (MSD,#R60TX-3) containing 1× halt protease & phosphatase inhibitor cocktail(Thermo Scientific, #0861281), 1 mM phenylmethanesulfonyl fluoride(PMSF) (Sigma, #93482-50ML-F) and 1 μM sodium metavanadate (Sigma,#590088) using Matrix D beads (MP Biomedical, #6913-500) in aFastPrep-24™ Cell Disrupter machine (MP Biomedical) in a cold room (4°C.). Transfer tumor lysates to fresh tubes after spinning at 14000 rpmfor 20 minutes at 4° C. Determine protein concentration of tumor or celllysates using Pierce BCA Protein Assay Kit (cat#23225, ThermoScientific). This kit contains three main components—(1) BCA Reagent A,containing sodium carbonate, sodium bicarbonate, bicinchoninic acid andsodium tartarate in 0.1 M sodium hydroxide, (2) BCA Reagent B,containing 4% cupric sulfate, and (3) Albumin standard ampules,containing 2 mg/mL in 0.9% saline and 0.05% sodium azide. In a 96-wellplate, add bovine serum albumin protein standard for a concentrationrange of 20-2000 ug/mL in 25 μL in duplicate wells to generate astandard curve. Add cell or tumor lysates diluted in 25 μL 1×PBS toduplicate test wells. Prepare working BCA reagent by adding 2% Reagent Bto Reagent A (2 mL of B+98 mL of A), mix well and add 200 μL to eachsample or standard. Mix well, cover the plate and incubate at 37° C. for30 minutes. Cool plate to room temperature and measure the absorbance ator near 562 nm on a plate reader (Envision plate reader from PerkinElmer). Subtract the average 562 nm absorbance measurement of the blankstandard replicates from the 562 nm measurements of all other individualstandard and unknown (cell or tumor lysate) sample replicates. Prepare astandard curve by plotting the average blank-corrected 562 nmmeasurement for each bovine serum albumin standard versus itsconcentration in μg/mL. Use the standard curve to determine the proteinconcentration of each unknown samples using curve-fit logarithms inMicrosoft Excel. Freeze remaining tumor lysates at −80° C. Use oncefreeze-thawed tumor lysates to measure pRSK1 expression by sandwichELISA.

Coat 96-well plates (Thermo, #15042) overnight at 4° C. with 40 ng ofRSK1 goat antibody (Santa Cruz, #sc-231-G) and incubate at roomtemperature for one hour and then at 4° C. overnight. Wash plates threetimes with 300 μL of PBST (1× phosphate buffered saline (PBS) containing0.05% Tween-20), block with 100 μL per well of blocking buffer (ThermoScientific, #37532) and incubated at room temperature for two hours.Wash plates three times with 300 μL PBST and transfer 20 μg of tumorlysate to each well and incubate at 4° C. overnight. Wash plates threetimes with 300 μL PB ST and incubate with 100 μL of pRSK1 (T359/5363)rabbit antibody (1:1000 dilution in blocking buffer) at room temperaturefor four hours. Wash plates three times with 300 μL PBST and incubatewith 100 μL anti-rabbit HRP-conjugated secondary antibody (GE HealthcareUK, #NA934V; diluted 1:10000 in blocking buffer) Incubate at roomtemperature for one hour. Wash plates three times with 300 μL of PBST,add 100 μL of SUPERSIGNAL® ELISA Femto maximum sensitivity substrate(Thermo, #37075) and incubate on a shaker for one minute. Determine theluminescence signal using an ENVISION® plate reader. Determine the pRSK1level in each tumor lysate by considering tumor lysates from animalstreated with vehicle alone as 100%. Analyze each sample in duplicate anduse average numbers for calculations. Calculate TED₅₀ using Excel and XLFit.

A compound within the scope of the invention is tested in this assaysubstantially as described above. The results of this assay demonstratesthat the compound of Example 1 inhibits RSK1 phosphorylation in a tumorxenograft model. For example, the compound of Example 1 has a TED₅₀value of 16 mg/kg.

Xenograft Tumor Models

The purpose of this assay is to measure reduction in tumor volume inresponse to test compound administration. Expand human colorectal cancercells HCT116 (ATCC, # CCL-247) in culture, harvest and inject 5×10e⁶cells in 200 μL of 1:1 HBSS+matrigel solution subcutaneously on to therear right flank of female athymic nude mice (22-25 g, HarlanLaboratories). Expand human pancreatic cancer cells MIA PACA-2 (ATCC, #CRL-1420) or human non-small cell lung cancer cells CALU-6 (ATCC,#HTB-56) or human colorectal cancer cells COLO-205 (ATCC, #CCL-222) inculture, harvest and inject 5×10e⁶ cells in 200 μL of 1:1 HBSS+matrigelsolution subcutaneously on to the rear right flank of female athymicnude mice (22-25 g, Harlan Laboratories). Measure tumor growth and bodyweight twice per week beginning the seventh day after the implantation.When tumor sizes reach 200-400 mm³, randomize animals and group intogroups of eight to ten animals. Prepare test compound in an appropriatevehicle (vehicle: 1% HEC/0.25% Tween 80/0.05% Antifoam) and administerby oral gavage for 14 to 21 days. Tumor response is determined by tumorvolume measurement performed twice a week during the course oftreatment. Body weight is taken as a general measure of toxicity.

A compound within the scope of invention is tested in this assay runsubstantially as above. The compound of Example 1 is found to have deltaT/C % values as provided in Table 2 below. These results indicate thatthe compound of Example 1 demonstrates significant anti-tumor activityin several human cancer xenograft models including HCT116, MIA PACA-2,CALU-6 and COLO-205.

TABLE 2 Efficacy of Example 1 in xenograft models Delta T/C Tumor Dose %or Model (mg/kg) Schedule p-value Regr % TGI % HCT116 25 QD −8 108HCT116 50 QD <0.001* 11 89 HCT116 100 QD <0.001* −25 125 MIA PACA- 12.5QD   0.003* 32 68 2 MIA PACA- 25 QD <0.001* 2 98 2 MIA PACA- 50 QD<0.001* −22 122 2 MIA PACA- 100 QD <0.001* −66 166 2 CALU-6 12.5 QD  0.010* 22 78 CALU-6 25 QD   0.005* 14 86 CALU-6 50 QD <0.001* −31 131CALU-6 100 QD <0.001* −77 177 COLO-205 12.5 QD <0.001* −19 119 COLO-20525 QD <0.001* −32 132 COLO-205 100 QD <0.001* −76 176 Analysis for tumorvolume is based on Log 10 and SpatialPower covariance structure. *:significant (p < 0.05) NA: Not applicable Delta T/C % is calculated whenthe endpoint tumor volume in a treated group is at or above baselinetumor volume. The formula is 100 * (T − T₀)/(C − C₀), where T and C aremean endpoint tumor volumes in the treated or control group,respectively. T₀ and C₀ are mean baseline tumor volumes in those groups.Regression % is calculated when the endpoint volume is below baseline.The formula is 100 * (T − T₀)/T₀ Where T₀ is the mean baseline tumorvolume for the treated group. For HCT116, MIA PACA-2 and CALU-6, models,grand mean of all groups from baseline (randomization) at day 10, day 20and day 15, respectively was used to compute % change of T/C.

In Vivo Combination Studies

Due to tumor heterogeneity combination therapy has become essential incertain types of cancer treatment for effective therapy or to overcomeacquired resistance. It is hypothesized that a combination of targetedtherapies has the potential to be more effective in slowing or evenhalting cancers. In that context, the compound of Example 1 is testedfor tumor growth inhibition in combination with a pan-RAF inhibitorcompound (see WO 2013/134243,1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea,hereinafter “the pan-RAF inhibitor compound”), a CDK4/6 inhibitorcompound (see WO 2010/075074,[5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine,or a pharmaceutically acceptable salt thereof), hereinafter “the CDK4/6inhibitor compound”), or DC101 (see, for example, Witte L., et al CancerMetastasis Rev., 17,155-161, 1998, rat monoclonal antibody directedagainst mouse VEGFR2 that may be used in experiments as a surrogate inmice for an anti-VEGFR2 Ab, preferably ramucirumab (see WO 2003/075840,also known as Cyramza®, IMC-1121b, CAS registry number 947687-13-0)).More specifically, the compound of Example 1 is tested in combinationwith either the pan-RAF inhibitor compound or the CDK4/6 inhibitorcompound in HCT116, a KRAS mutant colorectal cancer xenograft model.Also, the compound of Example 1 is tested in combination with either theCDK4/6 inhibitor compound or DC101 in NCI-H441, A549, and NCI-H2122,KRAS mutant non-small cell lung cancer (NSCLC) xenograft models.

The HCT116 combination efficacy study is done in athymic nude rats.Expand human colorectal cancer cells HCT116 (ATCC, #CCL-247) in culture,harvest and inject 5×10e⁶ cells in 200 μL of 1:1 HBSS+matrigel solutionsubcutaneously on to the rear right flank of female NIH nude rats(120-145 gm, Taconic Farms). Measure tumor growth and body weight twiceper week beginning the seventh day after the implantation. When averagetumor sizes reach 200-300 mm³, randomize animals and group into groupsof five to seven animals. Prepare test compound in an appropriatevehicle (see below) and administer by oral gavage for 21 to 28 days.Tumor response is determined by tumor volume measurement performed twicea week during the course of treatment. Vehicle used in this study is 1%HEC (hydroxy ethyl cellulose)/0.25% Tween® 80/0.05% Antifoam. Thecompound of Example 1 and the pan-RAF inhibitor compound are formulatedin 1% HEC/0.25% Tween® 80/0.05% Antifoam. The CDK4/6 inhibitor compoundis formulated in 1% HEC in 25 mM Sodium phosphate buffer, pH 2.Administration of the compound of Example 1 at 10 mpk and 20 mpk QDresults in single agent activity of 52% and 64% tumor growth inhibitionrespectively (Table 3). In contrast, administration of the pan-RAFinhibitor compound at 10 mpk and 20 mpk BID results in single agentactivity of 29% and 68%, respectively. All treatments are statisticallysignificant (p<0.05) from vehicle control except the pan-RAF inhibitorcompound at 10 mpk BID. Administration of the compound of Example 1 at10 mpk, QD in combination with the pan-RAF inhibitor compound at 10 mpk,BID results in 94% tumor growth inhibition (p<0.001) and the combinationresult is “Synergistic” as calculated by Bliss Independence method(Table 3). This combination appears to be tolerated as there is nosignificant body weight loss. Administration of the compound of Example1 at 10 mpk, QD in combination with the pan-RAF inhibitor compound at 20mpk, BID has also results in significant (p<0.05) tumor growthinhibition (95%) and the combination result is “Additive” “as calculatedby Bliss Independence method (Table 3). This combination appears to betolerated as there is no significant body weight loss. In the samestudy, administration of the compound of Example 1 at 10 mpk, QD withthe CDK4/6 inhibitor compound at 20 mpk QD results in 98% tumor growthinhibition whereas single agent efficacy of the compound of Example 1and the CDK4/6 inhibitor compound are 52% and 76% tumor growthinhibition, respectively. Combination of these two agents show astatistically significant “Additive” result as calculated by BlissIndependence method (Table 3). This combination appears to be toleratedas there is no significant body weight loss. These results suggest thatcombination of the compound of Example 1 with either thepan-RAFinhibitor compound or the CDK4/6 inhibitor compound may providegreater benefit to patients having KRAS mutant colorectal cancer.

TABLE 3 Combination studies of the compound of Example 1 with thepan-RAF inhibitor compound, or the CDK4/6 inhibitor compound in HCT116KRAS mutant colorectal cancer xenograft model Dose Delta TGI CombinationTreatment Compound (mg/kg) Schedule T/C % % p-value Result** 1 VehicleNA BID NA NA NA NA 2 Example 1 10 QD 48 52 0.038* NA 3 Example 1 20 QD36 64 0.005* NA 4 pan-RAF 10 BID 71 29 0.303 NA inhibitor 5 pan-RAF 20BID 32 68 0.001* NA inhibitor 6 CDK4/6 20 QD 24 76 <0.001* NA inhibitor7 Example 1 +  10, QD, 6 94 <0.001* Synergistc pan-RAF 10 BID inhibitor8 Example 1 +  10, QD, 5 95 <0.001* Additive pan-RAF 20 BID inhibitor 9Example 1 +  10, QD, CDK4/6 20 QD 2 98 <0.001* Additive inhibitorAnalysis for tumor volume is based on Log 10 and SpatialPower covariancestructure. *significant (p < 0.05) **The statistical effect of thecombination of two agents is determined by Bliss Independence method:First, a repeated measures model is fit to log tumor volume vs. group,time and group-by-time. Then contrast statements are used to test for aninteraction effect at each time point. The expected additive response(EAR) for the combination is calculated on the tumor volume scale as,EAR volume = V1 * V2/V0, where V0, V1, and V2 are the estimated meantumor volumes for the vehicle control, treatment 1 alone, and treatment2 alone, respectively. If the interaction test is significant (p <0.05), the combination effect is declared synergistic if the observedcombination volume is less than the EAR volume, antagonistic if theobserved combination volume is greater than the EAR volume, or additiveotherwise, at the doses and schedules that are tested. NA: Notapplicable Delta T/C % is calculated when the endpoint tumor volume in atreated group is at or above baseline tumor volume. The formula is 100 *(T − T₀)/(C − C₀), where T and C are mean endpoint tumor volumes in thetreated or control group, respectively. T₀ and C₀ are mean baselinetumor volumes in those groups. Dose for 28 days in all studies Grandmean of all groups from baseline (randomization) at day 11 was used tocompute % change of T/C

Combination efficacy is also tested in three KRAS mutant NSCLC xenograftmodels including A549 (KRAS_G12S) in SCID mice as well as NCI-H441(KRAS_G12V) and NCI-H2122 (KRAS_G12C) in athymic nude mice. Expand humannon-small cell lung cancer cells NCI-H441 (ATCC, #CRL-5807) andNCI-H2122 (ATCC, #CRL-5985) in culture, harvest and inject 5×10e⁶ cellsin 200 μL of 1:1 HBSS+matrigel solution subcutaneously on to the rearright flank of female athymic nude mice (20-22 gm, Harlan Laboratories).Expand human non-small cell lung cancer cells A549 (ATCC, #CC1-185) inculture, harvest and inject 5×10e⁶ cells in 200 μL of 1:1 HBSS+matrigelsolution subcutaneously on to the rear right flank of female CB-17 SCIDmice (18-20 gm, Taconic Farms). For all cell lines, measure tumor growthand body weight twice per week beginning the seventh day after theimplantation. When average tumor sizes reach 200-300 mm³, randomizeanimals and group into groups of five to seven animals. Prepare testcompound in an appropriate vehicle (see below) and administer by oralgavage (compound of Example 1 and the CDK4/6 inhibitor compound) orintraperitoneally (DC101) for 21 to 28 days. Tumor response isdetermined by tumor volume measurement performed twice a week during thecourse of treatment. Vehicle used in these studies is 1% HEC/0.25%Tween® 80/0.05% Antifoam. The compound of Example 1 is formulated in 1%HEC/0.25% Tween® 80/0.05% Antifoam and the CDK4/6 inhibitor compound isformulated in 1% HEC in 25 mM sodium phosphate buffer, pH 2. Theadministration of the compound of Example 1 as a single agent at 50 mpkresults in 41% and 91% tumor growth inhibition in NCI-H2122 and A549tumors respectively; and leads to 101% tumor growth inhibition (i.e., 1%tumor regression) in NCI-H441 tumors. Administration of the CDK4/6inhibitor compound as single agent at 50 mpk results in 53%, 51% and 81%tumor growth inhibition in NCI-H2122, A549 and NCI-H441 modelsrespectively. Also, the combination of the compound of Example 1 (50mpk) with the CDK4/6 inhibitor compound (50 mpk) results in 151% (i.e.51% regression) and 147% (i.e. 47% regression) tumor growth inhibitionin A549 and NCI-H441 tumors respectively; and 82% tumor growthinhibition in NCI-H2122 tumors. The combination result in all threetumor models are “Additive” as calculated by Bliss Independence method(Table 4). In general, all treatments appear to be tolerated in thesestudies as indicated by no significant body weight loss. In the sameNCI-H441 xenograft model, DC101 in phosphate buffer is also administeredintraperitoneally twice per week (BIW) as a single agent or incombination with the compound of Example 1, 50 mpk, QD for 28 days.Administration of DC101 at 20 mpk BIW results in a single agent activityof 102% tumor growth inhibition (i.e. 2% regression). Combination of thecompound of Example 1 at 50 mpk, QD with DC101 at 20 mpk, BIW results in146% tumor growth inhibition (i.e. 46% regression). This combinationresult is “Additive” as calculated by Bliss Independence method (Table4). This combination appears to be tolerated as there is no significantbody weight loss. These results suggest that combination of the compoundof Example 1 with either the CDK4/6 inhibitor compound or an anti-VEGFR2antibody may provide greater benefit to non-small cell lung cancerpatients with KRAS mutation.

TABLE 4 Combination studies of the compound of Example 1 with the CDK4/6inhibitor compound or DC101 in KRAS mutant non-small cell lung cancerxenograft models p-value Tumor Dose Delta Regression (vs. CombinationModel Treatment Compound (mg/kg) Schedule⁺ T/C % % Vehicle) Effect**NCI- 1 Vehicle NA QD NA NA NA NA H441 2 CDK4/6 50 QD 19 NA <0.001* NANSCLC inhibitor Model 3 DC101 20 BIW NA 2 <0.001* NA 4 Example 1 50 QDNA 1 <0.001* NA 5 Example 1 + 50 QD NA 46 <0.001* Additive DC101 20 BIW6 Example 1 + 50 QD NA 47 <0.001* Additive CDK4/6 50 QD inhibitor A549 1Vehicle NA QD NA NA NA NA NSCLC 2 CDK4/6 50 QD 49 NA 0.033* NA Modelinhibitor 3 Example 1 50 QD 9 NA <0.001* NA 4 Example 1 + 50 QD NA 51<0.001* Additive CDK4/6 50 QD inhibitor NCI- 1 Vehicle NA QD NA NA NA NAH2122 2 CDK4/6 50 QD 47 NA 0.008* NA NSCLC inhibitor Model 3 Example 150 QD 59 NA 0.055 NA 4 Example 1 + 50 QD 18 NA <0.001* Additive CDK4/650 QD inhibitor ⁺Analysis for tumor volume is based on Log 10transformation and a repeated measures ANOVA with a special powercovariance structure *significant (p < 0.05) **The statistical effect ofthe combination of two agents is determined by Bliss Independencemethod: First, a repeated measures model is fit to log tumor volume vs.group, time and group-by-time. Then contrast statements are used to testfor an interaction effect at each time point. The expected additiveresponse (EAR) for the combination is calculated on the tumor volumescale as, EAR volume = V1 * V2/V0, where V0, V1, and V2 are theestimated mean tumor volumes for the vehicle control, treatment 1 alone,and treatment alone, respectively. If the interaction test issignificant (p < 0.05), the combination effect is declared synergisticif the observed combination volume is less than the EAR volume,antagonistic if the observed combination volume is greater than the EARvolume, or additive otherwise, at the doses and schedules that aretested. NA: Not applicable Delta T/C % is calculated when the endpointtumor volume in a treated group is at or above baseline tumor volume.The formula is 100 * (T − T₀)/(C − C₀), where T₀ and C₀ are meanendpoint tumor volumes in the treated or control group, respectively. T₀and C₀ are mean baseline tumor volumes in those groups. Baseline(randomization) at day 11 (HCT116) , day 25 (NCI-H441), day 22 (A549),day 18 (NCI-H2122) are used to compute % change of T/C. Dose for 28 daysin all studies.

We claim:
 1. A compound of the formula:

wherein: R¹ is

R² and R³ are methyl or R² and R³ can be taken together to formcyclopropyl; R⁴ is hydrogen, methyl, chloro, fluoro, or trifluoromethyl;and R⁵ is

or a pharmaceutically acceptable salt thereof.
 2. The compound or saltaccording to claim 1 wherein R² and R³ are independently methyl.
 3. Thecompound or salt according to claim 2 wherein R⁴ is hydrogen.
 4. Thecompound or salt according to claim 3 wherein R¹ is


5. The compound or salt according to claim 3 wherein R⁵ is


6. The compound or salt according to claim 4 which is6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one.7. The compound according to claim 6 which is6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one.8. A pharmaceutical composition comprising a compound of the formula:

wherein: R¹ is

R² and R³ are methyl or R² and R³ can be taken together to formcyclopropyl; R⁴ is hydrogen, methyl, chloro, fluoro, or trifluoromethyl;and R⁵ is

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, diluent, or excipient.
 9. The pharmaceuticalcomposition according to claim 8 wherein R² and R³ are independentlymethyl.
 10. The pharmaceutical composition according to claim 9 whereinR⁴ is hydrogen.
 11. The pharmaceutical composition according to claim 10wherein R¹ is


12. The pharmaceutical composition according to claim 10 wherein R⁵ is


13. The pharmaceutical composition according to claim 11 which is6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one.14. The pharmaceutical composition according to claim 13 which is6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one.15. A method of treating cancer, comprising administering to a patientin need thereof, an effective amount of a compound of the formula:

wherein: R¹ is

R² and R³ are methyl or R² and R³ can be taken together to formcyclopropyl; R⁴ is hydrogen, methyl, chloro, fluoro, or trifluoromethyl;and R⁵ is

or a pharmaceutically acceptable salt thereof, wherein the cancer isselected from the group consisting of melanoma, colorectal cancer,pancreatic cancer, and non-small cell lung cancer.
 16. The methodaccording to claim 15 wherein R² and R³ are independently methyl. 17.The method according to claim 16 wherein R⁴ is hydrogen.
 18. The methodaccording to claim 17 wherein R¹ is


19. The compound or salt according to claim 17 wherein R⁵ is


20. The compound or salt according to claim 18 which is6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one.21. The compound according to claim 20 which is6,6-dimethyl-2-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-5-[2-(morpholin-4-yl)ethyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one.22. The method according to claim 15, wherein the cancer is colorectalcancer.
 23. The method according to claim 16, wherein the cancer iscolorectal cancer.
 24. The method according to claim 17, wherein thecancer is colorectal cancer.
 25. The method according to claim 18,wherein the cancer is colorectal cancer.
 26. The method according toclaim 19, wherein the cancer is colorectal cancer.
 27. The methodaccording to claim 20, wherein the cancer is colorectal cancer.
 28. Themethod according to claim 21, wherein the cancer is colorectal cancer.29. The method according to claim 15, wherein the cancer is pancreaticcancer.
 30. The method according to claim 16, wherein the cancer ispancreatic cancer.
 31. The method according to claim 17, wherein thecancer is pancreatic cancer.
 32. The method according to claim 18,wherein the cancer is pancreatic cancer.
 33. The method according toclaim 19, wherein the cancer is pancreatic cancer.
 34. The methodaccording to claim 20, wherein the cancer is pancreatic cancer.
 35. Themethod according to claim 21, wherein the cancer is pancreatic cancer.36. The method according to claim 15, wherein the cancer is non-smallcell lung cancer.
 37. The method according to claim 16, wherein thecancer is non-small cell lung cancer.
 38. The method according to claim17, wherein the cancer is non-small cell lung cancer.
 39. The methodaccording to claim 18, wherein the cancer is non-small cell lung cancer.40. The method according to claim 19, wherein the cancer is non-smallcell lung cancer.
 41. The method according to claim 20, wherein thecancer is non-small cell lung cancer.
 42. The method according to claim21, wherein the cancer is non-small cell lung cancer.